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Zeman M, Stefanik P, Rumanova VS, Okuliarova M. Interactive effects of light at night and high fructose intake on the central circadian clock and endocrine outputs in rats. Mol Cell Endocrinol 2025; 605:112559. [PMID: 40311860 DOI: 10.1016/j.mce.2025.112559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 04/01/2025] [Accepted: 04/29/2025] [Indexed: 05/03/2025]
Abstract
Light pollution is an increasing global environmental risk factor that contributes to the recent burden of metabolic diseases. The underlying mechanisms are not understood, but disruption of circadian control of physiological and behavioural processes may be involved. The negative consequences of chronodisruption can be augmented by co-exposure to high energy intake. Therefore, we investigated the individual and combined effects of artificial light at night (ALAN) and 10 % fructose in drinking water on the central clock in the suprachiasmatic nuclei (SCN) of the hypothalamus and circadian hormonal outputs in male rats. After 10 weeks of ALAN exposure and high fructose intake, the clockwork in the SCN was attenuated as indicated by eliminated day/night differences in the core clock gene Per1. Additionally, ALAN suppressed the daily variability and fructose induced upregulation of a gamma-aminobutyric acid-synthesising enzyme (GAD65), potentially affecting inhibitory neurotransmission in the SCN. ALAN and fructose additively inhibited plasma melatonin levels revealing excessive fructose intake as a chronodisruptive factor that can be potentiated by ALAN. In contrast to melatonin, daytime plasma testosterone concentrations were increased by high fructose and supressed by ALAN. Furthermore, high fructose intake elevated the plasma levels of two adipokines, leptin and adiponectin, but this response was absent specifically during the daytime in rats exposed to ALAN, indicating that ALAN reduced adipose tissue responsiveness. Our results document the complex consequences of ALAN and high fructose intake on endocrine control mechanisms that can have a long-term negative impact on metabolic health.
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Affiliation(s)
- Michal Zeman
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia.
| | - Peter Stefanik
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia
| | - Valentina Sophia Rumanova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia; Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience (NIN), An Institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, the Netherlands; Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Laboratory of Endocrinology, Amsterdam University Medical Centers, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam, the Netherlands
| | - Monika Okuliarova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia
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Tadas M, Wankhede N, Chandurkar P, Kotagale N, Umekar M, Katariya R, Waghade A, Kokare D, Taksande B. Postnatal propionic acid exposure disrupts hippocampal agmatine homeostasis leading to social deficits and cognitive impairment in autism spectrum disorder-like phenotype in rats. Pharmacol Biochem Behav 2025; 252:174030. [PMID: 40318701 DOI: 10.1016/j.pbb.2025.174030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by a range of symptoms including impaired social interaction and cognitive deficits. Although the exact pathogenesis of ASD is not well established, recent clinical findings suggest a decline in levels of biogenic amine agmatine in autistic patients. The present study was designed to investigate the impact of postnatal propionic acid (PPA) exposure on hippocampal agmatine homeostasis in male rat pups and to explore a new therapeutic intervention for ASD using agmatine as a biological target. PPA is commonly used in experimental models of ASD due to its ability to induce social deficits, cognitive impairments, and stereotyped behaviors, which closely resemble key characteristics of ASD. Male rat pups were administered with PPA via the intrahippocampal route bilaterally (25 μg/0.25 μl per side) on PND-21 to simulate the ASD phenotype, and its subsequent effect on the endogenous agmatinergic system. The influence of agmatine treatment and its endogenous modulation on ASD-like phenotypes was also investigated. Behavioral assessments revealed that PPA exposure reduced sociability and social preference, caused learning and memory impairment in the Morris water maze, increased anxiety-like behavior in the elevated plus maze, and reduced exploratory behavior in the hole board test. Neurochemical analyses showed a decrease in agmatine concentration and an increase in its degrading enzyme agmatinase in the hippocampus. PPA treatment altered the content of GABA, glutamate, TNF-α, IL-6, BDNF, and also resulted in increased astrogliosis and neurotoxicity within the hippocampus. Chronic agmatine treatment and its endogenous modulation ameliorated the behavioral and biochemical disruptions induced by PPA exposure. This study highlights the critical role of hippocampal agmatinergic pathway in the etiopathogenesis of ASD, positioning agmatine as a promising therapeutic target for its treatment.
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Affiliation(s)
- Manasi Tadas
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S. 441 002, India
| | - Nitu Wankhede
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S. 441 002, India
| | - Pranali Chandurkar
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S. 441 002, India
| | - Nandkishor Kotagale
- Government College of Pharmacy, Kathora Naka, VMV Road, Amravati, M.S. 444 604, India
| | - Milind Umekar
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S. 441 002, India
| | - Raj Katariya
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S. 441 002, India
| | - Akash Waghade
- Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, M.S. 440 033, India
| | - Dadasaheb Kokare
- Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, M.S. 440 033, India
| | - Brijesh Taksande
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S. 441 002, India.
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Afarinesh MR, Ahmadi BBM, Sabzalizadeh M, Golshan F, Sheibani V. Tactile stimulation and its impact on barrel cortex neuron receptive fields in whisker-deprived male rats. Physiol Behav 2025; 295:114911. [PMID: 40209871 DOI: 10.1016/j.physbeh.2025.114911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/05/2025] [Accepted: 04/07/2025] [Indexed: 04/12/2025]
Abstract
Understanding the enhancement of neuronal performance through the interaction of various sensory stimuli and evaluating how these interactions influence neuronal responses and sensorimotor behaviors is critical. This study investigates the simultaneous effects of tactile stimulation (TS) and sensory deprivation of whiskers on the receptive field properties of barrel cortex neurons in Wistar rats. Male rats were subjected to whisker deprivation (WD) or TS for 21 days from birth. Neuronal responses to controlled deflections of principal and adjacent whiskers were assessed using single-unit recordings from the barrel cortex. Results indicated that while WD reduced the excitatory receptive fields of neurons, the magnitude of ON and OFF responses returned to control group levels following TS, suggesting improved neuronal function. These findings demonstrate that tactile stimulation can compensate for deficits caused by sensory deprivation.
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Affiliation(s)
- Mohammad Reza Afarinesh
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran; Cognitive Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Bi Bi Marzieh Ahmadi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mansoureh Sabzalizadeh
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Faly Golshan
- Brain Health Lab, Department of Psychology and Health Studies, University of Saskatchewan, Saskatoon, Canada
| | - Vahid Sheibani
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran; Cognitive Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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Mokhtar Tawfeek ES, Aly Abou Elez Gawish S, Hamed WS, Asker SA. Construction of an animal model of autism based on interaction between cerebellar histological, immunohistochemical, and biochemical changes in adult male albino rat. Ultrastruct Pathol 2025; 49:39-57. [PMID: 39654093 DOI: 10.1080/01913123.2024.2438382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 11/01/2024] [Accepted: 12/02/2024] [Indexed: 01/02/2025]
Abstract
METHODS Twelve pregnant female rats were divided into a control group and a valproic acid (VPA) treated group (injected intraperitoneally on embryonic day 12 with 600 mg/kg body weight of VPA). Neurobehavioral tests were conducted on the offspring of both groups. The cerebellum was studied by light and electron microscopy as well as GFAP and caspase-3 immunohistochemical staining. RESULTS The VPA-treated group showed signs of neuronal degeneration, such as congested blood vessels, vacuolations, irregularly shrunken with dark small heterochromatic nuclei and numerous apoptotic blebs in the Purkinje and granule cells with vacuolated cerebellar glomeruli. The myelinated nerve fibers showed rarefaction and loss of their neurofilaments. GFAP and caspase-3 immune expression were significantly altered in the VPA-treated group. CONCLUSION The VPA rat model can serve as an excellent model of autism at the structural level, which may be used as a validated model in preclinical studies to evaluate novel drugs.
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Affiliation(s)
- Eman Saeed Mokhtar Tawfeek
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura National University, Gamasa, Egypt
| | - Salwa Aly Abou Elez Gawish
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Wafaa Saad Hamed
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Samar A Asker
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Delta University, Gamasa, Egypt
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Cezar LC, da Fonseca CCN, Klein MO, Kirsten TB, Felicio LF. Prenatal Valproic Acid Induces Autistic-Like Behaviors in Rats via Dopaminergic Modulation in Nigrostriatal and Mesocorticolimbic Pathways. J Neurochem 2025; 169:e16282. [PMID: 39801243 DOI: 10.1111/jnc.16282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 11/19/2024] [Accepted: 11/26/2024] [Indexed: 05/02/2025]
Abstract
Autism spectrum disorder (ASD) is a complex developmental disorder characterized by several behavioral impairments, especially in socialization, communication, and the occurrence of stereotyped behaviors. In rats, prenatal exposure to valproic acid (VPA) induces autistic-like behaviors. Previous studies by our group have suggested that the autistic-like phenotype is possibly related to dopaminergic system modulation because tyrosine hydroxylase (TH) expression was affected. The objective of the present study was to understand the dopaminergic role in autism. Wistar rats on gestational day 12.5 received VPA (400 mg/kg) and behaviors related to rat models of ASD were evaluated in juvenile offspring. Neurochemical and genetic dopaminergic components were studied in different brain areas of both juvenile and adult rats. Prenatal VPA-induced autistic-like behaviors in comparison to a control group: decreased maternal solicitations by ultrasonic vocalizations, cognitive inflexibility and stereotyped behavior in the T-maze test, decreased social interaction and play behavior, as well as motor hyperactivity. Prenatal VPA also decreased dopamine synthesis and activity in the striatum and prefrontal cortex, as well as dopamine transporter, D1 and D2 receptors, and TH expressions. Moreover, prenatal VPA increased TH+ immunoreactive neurons of the ventral tegmental area-substantia nigra complex. In conclusion, the dopaminergic hypoactivity associated with the behavioral impairments exhibited by the rats that received prenatal VPA suggests the important role of this system in the establishment of the characteristic symptoms of ASD in juvenile and adult males. Dopamine was demonstrated to be an important biomarker and a potential pharmacological target for ASD.
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Affiliation(s)
- Luana C Cezar
- Department of Pathology, School of Veterinary Medicine, University of São Paulo, Sao Paulo, Brazil
| | | | - Marianne O Klein
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
| | - Thiago B Kirsten
- Psychoneuroimmunology Laboratory, Program in Environmental and Experimental Pathology, Paulista University, Sao Paulo, Brazil
| | - Luciano F Felicio
- Department of Pathology, School of Veterinary Medicine, University of São Paulo, Sao Paulo, Brazil
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Tang Y, Wang C, Li Q, Liu G, Song D, Quan Z, Yan Y, Qing H. Neural Network Excitation/Inhibition: A Key to Empathy and Empathy Impairment. Neuroscientist 2024; 30:644-665. [PMID: 38347700 DOI: 10.1177/10738584231223119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2024]
Abstract
Empathy is an ability to fully understand and feel the mental states of others. We emphasize that empathy is elicited by the transmission of pain, fear, and sensory information. In clinical studies, impaired empathy has been observed in most psychiatric conditions. However, the precise impairment mechanism of the network systems on the pathogenesis of empathy impairment in psychiatric disorders is still unclear. Multiple lines of evidence suggest that disturbances in the excitatory/inhibitory balance in neurologic disorders are key to empathetic impairment in psychiatric disorders. Therefore, we here describe the roles played by the anterior cingulate cortex- and medial prefrontal cortex-dependent neural circuits and their impairments in psychiatric disorders, including anxiety, depression, and autism. In addition, we review recent studies on the role of microglia in neural network excitation/inhibition imbalance, which contributes to a better understanding of the neural network excitation/inhibition imbalance and may open up innovative psychiatric therapies.
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Affiliation(s)
- Yuanhong Tang
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Chunjian Wang
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Qingquan Li
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Gang Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Da Song
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Zhenzhen Quan
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Yan Yan
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hong Qing
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
- Department of Biology, Shenzhen MSU-BIT University, Shenzhen, China
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King C, Mali I, Strating H, Fangman E, Neyhard J, Payne M, Bossmann SH, Plakke B. Region-Specific Brain Volume Changes Emerge in Adolescence in the Valproic Acid Model of Autism and Parallel Human Findings. Dev Neurosci 2024; 47:68-80. [PMID: 38679020 PMCID: PMC11511791 DOI: 10.1159/000538932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 04/09/2024] [Indexed: 05/01/2024] Open
Abstract
INTRODUCTION Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication deficits, cognitive dysfunction, and stereotyped repetitive behaviors. Regional volume changes are commonly observed in individuals with ASD. To examine volumetric dysregulation across adolescence, the valproic acid (VPA) model was used to induce ASD-like phenotypes in rats. METHOD Regional volumes were obtained via magnetic resonance imaging at either postnatal day 28 or postnatal day 40 (P40), which correspond to early and late adolescence, respectively. RESULTS Consistent with prior research, VPA animals had reduced total brain volume compared to control animals. A novel outcome was that VPA animals had overgrown right hippocampi at P40. Differences in the pattern of development of the anterior cingulate cortex were also observed in VPA animals. Differences for the posterior cingulate were only observed in males, but not females. CONCLUSION These results demonstrate differences in region-specific developmental trajectories between control and VPA animals and suggest that the VPA model may capture regional volume changes consistent with human ASD. INTRODUCTION Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication deficits, cognitive dysfunction, and stereotyped repetitive behaviors. Regional volume changes are commonly observed in individuals with ASD. To examine volumetric dysregulation across adolescence, the valproic acid (VPA) model was used to induce ASD-like phenotypes in rats. METHOD Regional volumes were obtained via magnetic resonance imaging at either postnatal day 28 or postnatal day 40 (P40), which correspond to early and late adolescence, respectively. RESULTS Consistent with prior research, VPA animals had reduced total brain volume compared to control animals. A novel outcome was that VPA animals had overgrown right hippocampi at P40. Differences in the pattern of development of the anterior cingulate cortex were also observed in VPA animals. Differences for the posterior cingulate were only observed in males, but not females. CONCLUSION These results demonstrate differences in region-specific developmental trajectories between control and VPA animals and suggest that the VPA model may capture regional volume changes consistent with human ASD.
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Affiliation(s)
- Cole King
- Psychological Sciences, Kansas State University, Manhattan, KS, USA
| | - Ivina Mali
- Department of Chemistry, Kansas State University, Manhattan, KS, USA
| | - Hunter Strating
- Psychological Sciences, Kansas State University, Manhattan, KS, USA
| | | | - Jenna Neyhard
- Psychological Sciences, Kansas State University, Manhattan, KS, USA
| | - Macy Payne
- Department of Chemistry, Kansas State University, Manhattan, KS, USA
| | | | - Bethany Plakke
- Psychological Sciences, Kansas State University, Manhattan, KS, USA
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Savuca A, Chelaru IA, Balmus IM, Curpan AS, Nicoara MN, Ciobica AS. Toxicological Response of Zebrafish Exposed to Cocktails of Polymeric Materials and Valproic Acid. SUSTAINABILITY 2024; 16:2057. [DOI: 10.3390/su16052057] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Microplastic pollution represents an emerging problem of great interest in the public domain in the last decade; in addition, it overlaps with another delicate problem—pollution with pharmaceutical products that can have negative effects on the environment and people, even in small amounts. The main purpose of this study was to assess the biochemical and behavioral effects of exposure of adult zebrafish (Danio rerio) to polyethylene (PE), polypropylene (PP) and valproic acid (VPA), respectively to their mixtures—possible situations in natural aquatic environments. In terms of behavioral responses, sociability appears to be more impaired in the PP group after 5 days of exposure. The mechanisms affected are more those of swimming performance than of sociability. Even more, VPA increases presence in the arm with conspecifics but decreases mobility and locomotion, indicating a possible anxiety mechanism. The mixtures decrease the aggressiveness, especially in the case of the PE+VPA group, where it reaches a super low level compared to the control, which could endanger the species in nature. Regarding the anxiogenic effect, PP and PE act differently: if PE has an anxiogenic effect, on the opposite side is the PP group, which shows a bolder and more agitated behavior. All four variants showed behavioral changes indicative of toxicity from the first dose.
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Affiliation(s)
- Alexandra Savuca
- Doctoral School of Geosciences, Faculty of Geography and Geology, “Alexandru Ioan Cuza” University of Iași, Carol I Avenue, 20A, 700505 Iași, Romania
- Doctoral School of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Carol I Avenue, 20A, 700505 Iași, Romania
| | - Ionut-Alexandru Chelaru
- Doctoral School of Geosciences, Faculty of Geography and Geology, “Alexandru Ioan Cuza” University of Iași, Carol I Avenue, 20A, 700505 Iași, Romania
- Doctoral School of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Carol I Avenue, 20A, 700505 Iași, Romania
| | - Ioana-Miruna Balmus
- Doctoral School of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Carol I Avenue, 20A, 700505 Iași, Romania
- Department of Exact Sciences and Natural Sciences, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University of Iasi, Alexandru Lapusneanu Street, 26, 700057 Iasi, Romania
| | - Alexandrina-Stefania Curpan
- Doctoral School of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Carol I Avenue, 20A, 700505 Iași, Romania
| | - Mircea Nicusor Nicoara
- Doctoral School of Geosciences, Faculty of Geography and Geology, “Alexandru Ioan Cuza” University of Iași, Carol I Avenue, 20A, 700505 Iași, Romania
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Carol I Avenue, 20A, 700505 Iași, Romania
| | - Alin Stelian Ciobica
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Carol I Avenue, 20A, 700505 Iași, Romania
- Center of Biomedical Research, Romanian Academy, Iasi Branch, Teodor Codrescu 2, 700481 Iasi, Romania
- Academy of Romanian Scientists, 3 Ilfov, 050044 Bucharest, Romania
- Preclinical Department, Apollonia University, 700511 Iasi, Romania
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Zarate-Lopez D, Torres-Chávez AL, Gálvez-Contreras AY, Gonzalez-Perez O. Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder. Curr Neuropharmacol 2024; 22:260-289. [PMID: 37873949 PMCID: PMC10788883 DOI: 10.2174/1570159x22666231003121513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 08/30/2023] [Accepted: 08/30/2023] [Indexed: 10/25/2023] Open
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with increased prevalence and incidence in recent decades. Its etiology remains largely unclear, but it seems to involve a strong genetic component and environmental factors that, in turn, induce epigenetic changes during embryonic and postnatal brain development. In recent decades, clinical studies have shown that inutero exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug, is an environmental factor associated with an increased risk of ASD. Subsequently, prenatal VPA exposure in rodents has been established as a reliable translational model to study the pathophysiology of ASD, which has helped demonstrate neurobiological changes in rodents, non-human primates, and brain organoids from human pluripotent stem cells. This evidence supports the notion that prenatal VPA exposure is a valid and current model to replicate an idiopathic ASD-like disorder in experimental animals. This review summarizes and describes the current features reported with this animal model of autism and the main neurobiological findings and correlates that help elucidate the pathophysiology of ASD. Finally, we discuss the general framework of the VPA model in comparison to other environmental and genetic ASD models.
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Affiliation(s)
- David Zarate-Lopez
- Laboratory of Neuroscience, School of Psychology, University of Colima, Colima 28040, México
- Physiological Science Ph.D. Program, School of Medicine, University of Colima, Colima 28040, Mexico
| | - Ana Laura Torres-Chávez
- Laboratory of Neuroscience, School of Psychology, University of Colima, Colima 28040, México
- Physiological Science Ph.D. Program, School of Medicine, University of Colima, Colima 28040, Mexico
| | - Alma Yadira Gálvez-Contreras
- Department of Neuroscience, Centro Universitario de Ciencias de la Salud, University of Guadalajara, Guadalajara 44340, México
| | - Oscar Gonzalez-Perez
- Laboratory of Neuroscience, School of Psychology, University of Colima, Colima 28040, México
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Biosca-Brull J, Basaure P, Guardia-Escote L, Cabré M, Blanco J, Morales-Navas M, Sánchez-Santed F, Colomina MT. Environmental exposure to chlorpyrifos during gestation, APOE polymorphism and the risk on autistic-like behaviors. ENVIRONMENTAL RESEARCH 2023; 237:116969. [PMID: 37659636 DOI: 10.1016/j.envres.2023.116969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/04/2023] [Accepted: 08/22/2023] [Indexed: 09/04/2023]
Abstract
Autism spectrum disorder (ASD) encompasses several neurodevelopmental conditions characterized by communication and social impairment, as well as repetitive patterns of behavior. However, it can co-occur with other mental conditions such as anxiety. The massive use of chlorpyrifos (CPF) has been linked to the increased prevalence of developmental disorders. Likewise, ASD has also been closely linked to a wide variety of genetic factors. The aims of the present investigation are to study how gestational CPF exposure and APOE polymorphism affects communication skills, early development and mid-term anxiety-like behaviors, as well as, changes in gene expression related to the cholinergic system. C57BL/6J and humanized apoE3 and apoE4 homozygous mice were exposed to 0 or 1 mg/kg/day of CPF through the diet, from gestational day (GD) 12-18. In addition, a group of C57BL/6J females were injected subcutaneously with 300 mg/kg/day of valproic acid (VPA) on GD 12 and 13. This group was used as a positive control for studying some core and associated autism-like behaviors. Communication skills by means of ultrasonic vocalizations and physical/motor development were assessed during the preweaning period, whereas locomotor activity, anxiety-like behaviors and the gene expression of cholinergic elements were evaluated during adolescence. Our results showed that C57BL/6J mice prenatally exposed to CPF or VPA showed a decrease in body weight and a delay in eye opening. Communication and anxiety behavior were affected differently depending on treatment, while gene expression was altered by sex and treatment. In addition, none of the parameters evaluated in apoE transgenic mice exposed to CPF were affected, but there were differences between genotypes. Therefore, we suggest that prenatal CPF exposure and VPA produce divergent effects on communication and anxiety.
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Affiliation(s)
- Judit Biosca-Brull
- Universitat Rovira i Virgili, Research Group in Neurobehavior and Health (NEUROLAB), Tarragona, Spain; Universitat Rovira i Virgili, Department of Psychology and Research Center for Behavior Assessment (CRAMC), Tarragona, Spain; Universitat Rovira i Virgili, Center of Environmental, Food and Toxicological Technology (TECNATOX), Reus, Spain.
| | - Pia Basaure
- Universitat Rovira i Virgili, Research Group in Neurobehavior and Health (NEUROLAB), Tarragona, Spain
| | - Laia Guardia-Escote
- Universitat Rovira i Virgili, Research Group in Neurobehavior and Health (NEUROLAB), Tarragona, Spain
| | - Maria Cabré
- Universitat Rovira i Virgili, Research Group in Neurobehavior and Health (NEUROLAB), Tarragona, Spain; Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, Tarragona, Spain
| | - Jordi Blanco
- Universitat Rovira i Virgili, Research Group in Neurobehavior and Health (NEUROLAB), Tarragona, Spain; Universitat Rovira i Virgili, Center of Environmental, Food and Toxicological Technology (TECNATOX), Reus, Spain; Universitat Rovira i Virgili, Department of Basic Medical Sciences, Reus, Spain
| | - Miguel Morales-Navas
- Department of Psychology, Health Research Center (CEINSA), Almeria University, 04120, Almeria, Spain
| | - Fernando Sánchez-Santed
- Department of Psychology, Health Research Center (CEINSA), Almeria University, 04120, Almeria, Spain
| | - Maria Teresa Colomina
- Universitat Rovira i Virgili, Research Group in Neurobehavior and Health (NEUROLAB), Tarragona, Spain; Universitat Rovira i Virgili, Department of Psychology and Research Center for Behavior Assessment (CRAMC), Tarragona, Spain; Universitat Rovira i Virgili, Center of Environmental, Food and Toxicological Technology (TECNATOX), Reus, Spain.
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11
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Abdel-Haq M, Ojha SK, Hamoudi W, Kumar A, Tripathi MK, Khaliulin I, Domb AJ, Amal H. Effects of extended-release 7-nitroindazole gel formulation treatment on the behavior of Shank3 mouse model of autism. Nitric Oxide 2023; 140-141:41-49. [PMID: 37714296 DOI: 10.1016/j.niox.2023.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/17/2023]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral deficits such as abnormalities in communication, social interaction, anxiety, and repetitive behavior. We have recently shown that the Shank3 mutation in mice representing a model of ASD causes excessive nitric oxide (NO) levels and aberrant protein S-nitrosylation. Further, 10-day daily injections of 7-NI, a neuronal nitric oxide synthase inhibitor, into Shank3Δ4-22 and Cntnap2(-/-) mutant mice (models of ASD) at a dose of 80 mg/kg reversed the manifestations of ASD phenotype. In this study, we proposed an extended release of 7-NI using a novel drug system. Importantly, unlike the intraperitoneal injections, our new preparation of poly (sebacic acid-co-ricinoleic acid) (PSARA) gel containing 7-NI was injected subcutaneously into the mutant mice only once. The animals underwent behavioral testing starting from day 3 post-injection. It should be noted that the developed PSARA gel formulation allowed a slow release of 7-NI maintaining the plasma level of the drug at ∼45 μg/ml/day. Further, we observed improved memory and social interaction and reduced anxiety-like behavior in Shank3 mutant mice. This was accompanied by a reduction in 3-nitrotyrosine levels (an indicator of nitrative/nitrosative stress) in plasma. Overall, we suggest that our single-dose formulation of PSARA gel is very efficient in rendering a therapeutic effect of 7-NI for at least 10 days. This approach may provide in the future a rational design of an effective ASD treatment using 7-NI and its clinical translation.
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Affiliation(s)
- Muhammad Abdel-Haq
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel
| | - Shashank Kumar Ojha
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel
| | - Wajeha Hamoudi
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel
| | - Awanish Kumar
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel
| | - Manish Kumar Tripathi
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel
| | - Igor Khaliulin
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel
| | - Abraham J Domb
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel.
| | - Haitham Amal
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel.
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12
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Habib MZ, Elnahas EM, Aboul-Ela YM, Ebeid MA, Tarek M, Sadek DR, Negm EA, Abdelhakam DA, Aboul-Fotouh S. Risperidone impedes glutamate excitotoxicity in a valproic acid rat model of autism: Role of ADAR2 in AMPA GluA2 RNA editing. Eur J Pharmacol 2023; 955:175916. [PMID: 37460052 DOI: 10.1016/j.ejphar.2023.175916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/13/2023] [Accepted: 07/14/2023] [Indexed: 07/28/2023]
Abstract
Several reports indicate a plausible role of calcium (Ca2+) permeable AMPA glutamate receptors (with RNA hypo-editing at the GluA2 Q/R site) and the subsequent excitotoxicity-mediated neuronal death in the pathogenesis of a wide array of neurological disorders including autism spectrum disorder (ASD). This study was designed to examine the effects of chronic risperidone treatment on the expression of adenosine deaminase acting on RNA 2 (Adar2), the status of AMPA glutamate receptor GluA2 editing, and its effects on oxidative/nitrosative stress and excitotoxicity-mediated neuronal death in the prenatal valproic acid (VPA) rat model of ASD. Prenatal VPA exposure was associated with autistic-like behaviors accompanied by an increase in the apoptotic marker "caspase-3" and a decrease in the antiapoptotic marker "BCL2" alongside a reduction in the Adar2 relative gene expression and an increase in GluA2 Q:R ratio in the hippocampus and the prefrontal cortex. Risperidone, at doses of 1 and 3 mg, improved the VPA-induced behavioral deficits and enhanced the Adar2 relative gene expression and the subsequent GluA2 subunit editing. This was reflected on the cellular level where risperidone impeded VPA-induced oxidative/nitrosative stress and neurodegenerative changes. In conclusion, the present study confirms a possible role for Adar2 downregulation and the subsequent hypo-editing of the GluA2 subunit in the pathophysiology of the prenatal VPA rat model of autism and highlights the favorable effect of risperidone on reversing the RNA editing machinery deficits, giving insights into a new possible mechanism of risperidone in autism.
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Affiliation(s)
- Mohamed Z Habib
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Esraa M Elnahas
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Yasmin M Aboul-Ela
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mai A Ebeid
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Marwa Tarek
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Doaa R Sadek
- Histology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Eman A Negm
- Histology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Dina A Abdelhakam
- Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sawsan Aboul-Fotouh
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Clinical Pharmacology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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13
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Barzegari A, Mahdirejei HA, Hanani M, Esmaeili MH, Salari AA. Adolescent swimming exercise following maternal valproic acid treatment improves cognition and reduces stress-related symptoms in offspring mice: Role of sex and brain cytokines. Physiol Behav 2023; 269:114264. [PMID: 37295664 DOI: 10.1016/j.physbeh.2023.114264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 05/20/2023] [Accepted: 06/06/2023] [Indexed: 06/12/2023]
Abstract
Valproic acid (VPA) treatment during pregnancy is a risk factor for developing autism spectrum disorder, cognitive deficits, and stress-related disorders in children. No effective therapeutic strategies are currently approved to treat or manage core symptoms of autism. Active lifestyles and physical activity are closely associated with health and quality of life during childhood and adulthood. This study aimed to evaluate whether swimming exercise during adolescence can prevent the development of cognitive dysfunction and stress-related disorders in prenatally VPA-exposed mice offspring. Pregnant mice received VPA, afterwards, offspring were subjected to swimming exercise. We assessed neurobehavioral performances and inflammatory cytokines (interleukin-(IL)6, tumor-necrosis-factor-(TNF)α, interferon-(IFN)γ, and IL-17A) in the hippocampus and prefrontal cortex of offspring. Prenatal VPA treatment increased anxiety-and anhedonia-like behavior and decreased social behavior in male and female offspring. Prenatal VPA exposure also increased behavioral despair and reduced working and recognition memory in male offspring. Although prenatal VPA increased hippocampal IL-6 and IFN-γ, and prefrontal IFN-γ and IL-17 in males, it only increased hippocampal TNF-α and IFN-γ in female offspring. Adolescent exercise made VPA-treated male and female offspring resistant to anxiety-and anhedonia-like behavior in adulthood, whereas it only made VPA-exposed male offspring resistant to behavioral despair, social and cognitive deficits in adulthood. Exercise reduced hippocampal IL-6, TNF-α, IFN-γ, and IL-17, and prefrontal IFN-γ and IL-17 in VPA-treated male offspring, whereas it reduced hippocampal TNF-α and IFN-γ in VPA-treated female offspring. This study suggests that adolescent exercise may prevents the development of stress-related symptoms, cognitive deficits, and neuroinflammation in prenatally VPA-exposed offspring mice.
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Affiliation(s)
- Ali Barzegari
- Department of Exercise Physiology, Payame Noor University (PNU), Tehran, Iran
| | | | - Masoumeh Hanani
- Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, Kish International Campus, University of Tehran, Kish, Iran
| | | | - Ali-Akbar Salari
- Salari Institute of Cognitive and Behavioral Disorders (SICBD), Karaj, Alborz, Iran; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
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14
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Viana CE, Bortolotto VC, Araujo SM, Dahleh MMM, Machado FR, de Souza Pereira A, Moreira de Oliveira BP, Leimann FV, Gonçalves OH, Prigol M, Guerra GP. Lutein-loaded nanoparticles reverse oxidative stress, apoptosis, and autism spectrum disorder-like behaviors induced by prenatal valproic acid exposure in female rats. Neurotoxicology 2023; 94:223-234. [PMID: 36528186 DOI: 10.1016/j.neuro.2022.12.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/10/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and repetitive behaviors. In this study, we assessed the effect of lutein-loaded nanoparticles on ASD-like behaviors induced by prenatal valproic acid (VPA) exposure in female offspring rats and the possible involvement of oxidative stress and apoptosis. Pregnant female Wistar rats received a single intraperitoneal injection of VPA (600 mg/kg), on the gestational day 12.5. The VPA-exposed female offspring rats were divided into two subgroups and received either lutein-loaded nanoparticles (5 mg/kg) or saline by oral gavage, for 14 days. The animals were submitted to the three-chamber test and open field to evaluate ASD-like behaviors. The hippocampus was removed for the determination of oxidative stress indicators (ROS; TBARS; SOD and Nrf2) and apoptosis biomarkers (Hsp-70; p38-MAPK; Bax and Bcl-2). The exposure to lutein-loaded nanoparticles reversed sociability deficit, social memory deficit, and anxiety-like and repetitive behaviors induced by VPA, and restored the oxidative stress indicators and apoptosis biomarkers in the hippocampus. This neurochemical effect must be associated with the reversal of ASD-like behaviors. These results provide evidence that lutein-loaded nanoparticles are an alternative treatment for VPA-induced behavioral damage in female rats and suggest the involvement of oxidative stress.
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Affiliation(s)
- Cristini Escobar Viana
- Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio, Universidade Federal do Pampa, Campus Itaqui, 97650-000 Itaqui, RS, Brazil; Programa de Pós-Graduação em Bioquímica, Universidade Federal do Pampa, Campus Uruguaiana, 97508-000 Uruguaiana, RS, Brazil
| | - Vandreza Cardoso Bortolotto
- Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio, Universidade Federal do Pampa, Campus Itaqui, 97650-000 Itaqui, RS, Brazil; Programa de Pós-Graduação em Bioquímica, Universidade Federal do Pampa, Campus Uruguaiana, 97508-000 Uruguaiana, RS, Brazil
| | - Stífani Machado Araujo
- Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio, Universidade Federal do Pampa, Campus Itaqui, 97650-000 Itaqui, RS, Brazil; Programa de Pós-Graduação em Bioquímica, Universidade Federal do Pampa, Campus Uruguaiana, 97508-000 Uruguaiana, RS, Brazil
| | - Mustafa Munir Mustafa Dahleh
- Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio, Universidade Federal do Pampa, Campus Itaqui, 97650-000 Itaqui, RS, Brazil
| | - Franciéle Romero Machado
- Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio, Universidade Federal do Pampa, Campus Itaqui, 97650-000 Itaqui, RS, Brazil; Programa de Pós-Graduação em Bioquímica, Universidade Federal do Pampa, Campus Uruguaiana, 97508-000 Uruguaiana, RS, Brazil
| | - Adson de Souza Pereira
- Programa de Pós-Graduação em Bioquímica, Universidade Federal do Pampa, Campus Uruguaiana, 97508-000 Uruguaiana, RS, Brazil
| | - Byanca Pereira Moreira de Oliveira
- Programa de Pós-Graduação em Tecnologia de Alimentos, Universidade Tecnológica Federal do Paraná, Campus Campo Mourão, 87301-006 Campo Mourão, PR, Brazil
| | - Fernanda Vitória Leimann
- Programa de Pós-Graduação em Tecnologia de Alimentos, Universidade Tecnológica Federal do Paraná, Campus Campo Mourão, 87301-006 Campo Mourão, PR, Brazil; Centro de Investigação de Montanha (CIMO), ESA, Instituto Politécnico de Bragança, Campus Santa Apolónia, 5300-253 Bragança, Portugal
| | - Odinei Hess Gonçalves
- Programa de Pós-Graduação em Tecnologia de Alimentos, Universidade Tecnológica Federal do Paraná, Campus Campo Mourão, 87301-006 Campo Mourão, PR, Brazil; Centro de Investigação de Montanha (CIMO), ESA, Instituto Politécnico de Bragança, Campus Santa Apolónia, 5300-253 Bragança, Portugal
| | - Marina Prigol
- Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio, Universidade Federal do Pampa, Campus Itaqui, 97650-000 Itaqui, RS, Brazil; Programa de Pós-Graduação em Bioquímica, Universidade Federal do Pampa, Campus Uruguaiana, 97508-000 Uruguaiana, RS, Brazil
| | - Gustavo Petri Guerra
- Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas - LaftamBio, Universidade Federal do Pampa, Campus Itaqui, 97650-000 Itaqui, RS, Brazil; Programa de Pós-Graduação em Bioquímica, Universidade Federal do Pampa, Campus Uruguaiana, 97508-000 Uruguaiana, RS, Brazil.
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15
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Li Q, Shi Y, Li X, Yang Y, Zhang X, Xu L, Ma Z, Wang J, Fan L, Wu L. Proteomic-Based Approach Reveals the Involvement of Apolipoprotein A-I in Related Phenotypes of Autism Spectrum Disorder in the BTBR Mouse Model. Int J Mol Sci 2022; 23:ijms232315290. [PMID: 36499620 PMCID: PMC9737945 DOI: 10.3390/ijms232315290] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/26/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder. Abnormal lipid metabolism has been suggested to contribute to its pathogenesis. Further exploration of its underlying biochemical mechanisms is needed. In a search for reliable biomarkers for the pathophysiology of ASD, hippocampal tissues from the ASD model BTBR T+ Itpr3tf/J (BTBR) mice and C57BL/6J mice were analyzed, using four-dimensional (4D) label-free proteomic analysis and bioinformatics analysis. Differentially expressed proteins were significantly enriched in lipid metabolic pathways. Among them, apolipoprotein A-I (ApoA-I) is a hub protein and its expression was significantly higher in the BTBR mice. The investigation of protein levels (using Western blotting) also confirmed this observation. Furthermore, expressions of SphK2 and S1P in the ApoA-I pathway both increased. Using the SphK inhibitor (SKI-II), ASD core phenotype and phenotype-related protein levels of P-CREB, P-CaMKII, and GAD1 were improved, as shown via behavioral and molecular biology experiments. Moreover, by using SKI-II, we found proteins related to the development and function of neuron synapses, including ERK, caspase-3, Bax, Bcl-2, CDK5 and KCNQ2 in BTBR mice, whose levels were restored to protein levels comparable to those in the controls. Elucidating the possible mechanism of ApoA-I in ASD-associated phenotypes will provide new ideas for studies on the etiology of ASD.
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Mishra A, Singla R, Kumar R, Sharma A, Joshi R, Sarma P, Kaur G, Prajapat M, Bhatia A, Medhi B. Granulocyte Colony-Stimulating Factor Improved Core Symptoms of Autism Spectrum Disorder via Modulating Glutamatergic Receptors in the Prefrontal Cortex and Hippocampus of Rat Brains. ACS Chem Neurosci 2022; 13:2942-2961. [PMID: 36166499 DOI: 10.1021/acschemneuro.2c00270] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Chronic neuroinflammation-induced anomalous glutamate receptor activation has been identified as one of the important factors in the pathogenesis of autism spectrum disorder (ASD). Thus, the current study was designed to elucidate the neuroprotective effect of the granulocyte colony-stimulating factor (G-CSF), a haemopoietic growth factor, an anti-inflammatory, and a neuroprotectant to decipher the underlying mechanism(s) in the valproic acid (VPA)-induced experimental model of ASD. Experimentally, the ASD rat model was induced by a single dose of VPA (600 mg/kg; i.p.) on gestation day 12.5 to the pregnant female rats. After birth, pups were treated with vehicle, normal saline 0.9% i.p., risperidone (2.5 mg/kg; i.p.), and G-CSF (10, 35, and 70 μg/kg; i.p.) from postnatal day (PND) 23 to 43. All the groups were subjected to various developmental and behavior tests from birth. The rats were sacrificed on PND 55, and their brain was excised and processed for biochemical parameters (oxidative stress, inflammatory markers, BDNF), histological examination (H&E, Nissl staining), NMDA, and AMPA receptor expression by immunohistochemistry, western blot, and real-time polymerase chain reaction evaluation. Also, the possible interaction of the G-CSF with NMDA and AMPA receptors was evaluated using the in-silico method. The results of the study showed that in VPA-exposed rats, postnatal treatment of G-CSF rescued all the behavioral abnormalities, oxidative stress, and inflammatory parameters in a dose-dependent manner while risperidone did not show any significant results. The in-silico analysis showed the direct interaction of G-CSF with NMDA and AMPA receptors. The upregulated expression of NMDA and AMPA both in the prefrontal cortex as well as hippocampus was alleviated by G-CSF thereby validating its anti-inflammatory and excitoprotective properties. Thus, G-CSF demonstrated neuroprotection against the core symptoms of autism in the VPA-induced rodent model, making it a potential candidate for the treatment of ASD.
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Affiliation(s)
- Abhishek Mishra
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Rubal Singla
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Rohit Kumar
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - AmitRaj Sharma
- Department of Neurology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Rupa Joshi
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Phulen Sarma
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Gurjeet Kaur
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Manisha Prajapat
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Alka Bhatia
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
| | - Bikash Medhi
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India
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Mansour Y, Burchell A, Kulesza R. Abnormal vestibular brainstem structure and function in an animal model of autism spectrum disorder. Brain Res 2022; 1793:148056. [PMID: 35985362 DOI: 10.1016/j.brainres.2022.148056] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 08/11/2022] [Indexed: 11/25/2022]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes several key neuropathological changes and behavioral impairments. In utero exposure to the anti-epileptic valproic acid (VPA) increases risk of an ASD diagnosis in human subjects and timed in utero exposure to VPA is a clinically relevant animal model of ASD. Many human subjects with ASD have cerebellar hypoplasia, fewer Purkinje cells, difficulties with balance, ophthalmic dysfunction and abnormal responses to vestibular stimulation and such vestibular difficulties are likely under reported in ASD. We have recently shown that animals exposed to VPA in utero have fewer neurons in their auditory brainstem, reduced axonal projections to the auditory midbrain and thalamus, reduced expression of the calcium binding protein calbindin (CB) in the brainstem and cerebellum, smaller and occasionally ectopic cerebellar Purkinje cells and ataxia on several motor tasks. Based on these findings, we hypothesized that in utero VPA exposure similarly impacts structure and function of the vestibular brainstem. We investigated this hypothesis using quantitative morphometric analyses, immunohistochemistry for CB, a battery of vestibular challenges, recording of vestibular-evoked myogenic potentials and spontaneous eye movements. Our results indicate that VPA exposure results in fewer neurons in the vestibular nuclei, fewer CB-positive puncta, difficulty on certain motor tasks, longer latency VEMPs and significantly more horizontal eye movements. These findings indicate that the vestibular nuclei are impacted by in utero VPA exposure and provide a basis for further study of vestibular circuits in human cases of ASD.
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Affiliation(s)
- Yusra Mansour
- Department of Anatomy, Lake Erie College of Osteopathic Medicine, Erie, PA, United States; Henry Ford Macomb Hospital, Department of Otolaryngology - Head and Neck Surgery, Clinton Township, MI, United States
| | - Alyson Burchell
- Department of Anatomy, Lake Erie College of Osteopathic Medicine, Erie, PA, United States
| | - Randy Kulesza
- Department of Anatomy, Lake Erie College of Osteopathic Medicine, Erie, PA, United States.
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Podgorac J, Sekulić S, Petković B, Stojadinović G, Martać L, Pešić V. The influence of continuous prenatal exposure to valproic acid on physical, nociceptive, emotional and psychomotor responses during adolescence in mice: Dose-related effects within sexes. Front Behav Neurosci 2022; 16:982811. [PMID: 36248030 PMCID: PMC9557044 DOI: 10.3389/fnbeh.2022.982811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/31/2022] [Indexed: 11/23/2022] Open
Abstract
Clinical findings show that the use of valproic acid (VPA) during pregnancy increases the risk of birth defects and autism spectrum disorder in offspring. Although there is a consensus that monitoring of potential long-term outcomes of VPA exposure is needed, especially in undiagnosed individuals, preclinical studies addressing this issue are rare. The present study examined the effects of continuous intrauterine exposure to a wide dose range of VPA (50, 100, 200, and 400 mg/kg/day) on the physical and behavioral response in peripubertal mice as a rodent model of adolescence. Body weight and the hot plate test [on postnatal days (PND) 25 and 32], the elevated plus-maze test (on PND35), and the open field test (on PND40) served to examine physical growth, the supraspinal reflex response to a painful thermal stimulus and conditional learning, anxiety-like/risk-assessment behavior, as well as novelty-induced psychomotor activity, respectively. VPA exposure produced the following responses: (i) a negative effect on body weight, except for the dose of 100 mg/kg/day in both sexes; (ii) an increase in the percentage of animals that responded to the thermal stimulus above the defined cut-off time interval and the response latency in both sexes; (iii) dose-specific changes within sexes in behavior provoked by a novel anxiogenic environment, i.e., in females less anxiety-like/risk-assessment behavior in response to the lowest exposure dose, and in males more pronounced anxiety-like/risk-assessment behavior after exposure to the highest dose and 100 mg/kg/day; (iv) dose-specific changes within sexes in novelty-induced psychomotor activity, i.e., in females a decrease in stereotypy-like activity along with an increase in rearing, and in males a decrease in stereotypy-like activity only. These findings show that continuous intrauterine exposure to VPA produces maladaptive functioning in different behavioral domains in adolescence and that the consequences are delicate to assess as they are dose-related within sexes.
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Affiliation(s)
- Jelena Podgorac
- Department of Neurophysiology, Institute for Biological Research “Siniša Stanković” – National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Slobodan Sekulić
- Faculty of Medicine Novi Sad, University of Novi Sad, Novi Sad, Serbia
- Department of Neurology, Clinical Center of Vojvodina, Novi Sad, Serbia
| | - Branka Petković
- Department of Neurophysiology, Institute for Biological Research “Siniša Stanković” – National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Gordana Stojadinović
- Department of Neurophysiology, Institute for Biological Research “Siniša Stanković” – National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Ljiljana Martać
- Department of Neurophysiology, Institute for Biological Research “Siniša Stanković” – National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Vesna Pešić
- Department of Neurobiology, Institute for Biological Research “Siniša Stanković” – National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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19
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Ma SY, KWAN KM. Size Anomaly and Alteration of GABAergic Enzymes Expressions in Cerebellum of a Valproic acid Mouse Model of Autism. Behav Brain Res 2022; 428:113896. [DOI: 10.1016/j.bbr.2022.113896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 03/29/2022] [Accepted: 04/13/2022] [Indexed: 11/02/2022]
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20
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Shi WQ, Zhang MX, Tang LY, Ye L, Zhang YQ, Lin Q, Li B, Shao Y, Yu Y. Altered spontaneous brain activity patterns in patients with diabetic retinopathy using amplitude of low-frequency fluctuation. World J Diabetes 2022; 13:97-109. [PMID: 35211247 PMCID: PMC8855138 DOI: 10.4239/wjd.v13.i2.97] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 08/10/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetes mellitus is a metabolic disorder characterized by prolonged elevation of blood glucose due to various causes. Currently, the relationship between diabetic retinopathy (DR) and altered connectivity of brain function is unclear.
AIM To investigate the relationship between this brain activity and clinical manifestations and behaviors of DR patients by using the amplitude of low-frequency fluctuation (ALFF) technique.
METHODS Twenty-four DR patients and 24 healthy controls (HCs) matched for age and gender were enrolled. We measured and recorded average ALFF values of DR patients and HCs and then classified them using receiver operating characteristic (ROC) curves.
RESULTS ALFF values of both left and right posterior cerebellar lobe and right anterior cingulate gyrus were remarkably higher in the DR patients than in the HCs; however, DR patients had lower values in the bilateral calcarine area. ROC curve analysis of different brain regions demonstrated high accuracy in the area under the curve analysis. There was no significant relationship between mean ALFF values for different regions and clinical presentations in DR patients. Neuronal synchronization abnormalities in some brain regions of DR patients were associated with cognitive and visual disorders.
CONCLUSION Abnormal spontaneous brain activity was observed in many areas of DR patients’ brains, which may suggest a possible link between clinical manifestations and behaviors in DR patients.
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Affiliation(s)
- Wen-Qing Shi
- Department of Endocrinology and Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi clinical research center for endocrine and metabolic disease, Nanchang 330006, Jiangxi Province, China
| | - Mou-Xin Zhang
- Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, Fujian Province, China
| | - Li-Ying Tang
- Department of Ophthalmology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, Fujian Province, China
| | - Lei Ye
- Department of Endocrinology and Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi clinical research center for endocrine and metabolic disease, Nanchang 330006, Jiangxi Province, China
| | - Yu-Qing Zhang
- Department of Endocrinology and Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi clinical research center for endocrine and metabolic disease, Nanchang 330006, Jiangxi Province, China
| | - Qi Lin
- Department of Endocrinology and Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi clinical research center for endocrine and metabolic disease, Nanchang 330006, Jiangxi Province, China
| | - Biao Li
- Department of Endocrinology and Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi clinical research center for endocrine and metabolic disease, Nanchang 330006, Jiangxi Province, China
| | - Yi Shao
- Department of Endocrinology and Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi clinical research center for endocrine and metabolic disease, Nanchang 330006, Jiangxi Province, China
| | - Yao Yu
- Department of Endocrinology and Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi clinical research center for endocrine and metabolic disease, Nanchang 330006, Jiangxi Province, China
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21
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Zhao H, Mao X, Zhu C, Zou X, Peng F, Yang W, Li B, Li G, Ge T, Cui R. GABAergic System Dysfunction in Autism Spectrum Disorders. Front Cell Dev Biol 2022; 9:781327. [PMID: 35198562 PMCID: PMC8858939 DOI: 10.3389/fcell.2021.781327] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/16/2021] [Indexed: 12/19/2022] Open
Abstract
Autism spectrum disorder (ASD) refers to a series of neurodevelopmental diseases characterized by two hallmark symptoms, social communication deficits and repetitive behaviors. Gamma-aminobutyric acid (GABA) is one of the most important inhibitory neurotransmitters in the central nervous system (CNS). GABAergic inhibitory neurotransmission is critical for the regulation of brain rhythm and spontaneous neuronal activities during neurodevelopment. Genetic evidence has identified some variations of genes associated with the GABA system, indicating an abnormal excitatory/inhibitory (E/I) neurotransmission ratio implicated in the pathogenesis of ASD. However, the specific molecular mechanism by which GABA and GABAergic synaptic transmission affect ASD remains unclear. Transgenic technology enables translating genetic variations into rodent models to further investigate the structural and functional synaptic dysregulation related to ASD. In this review, we summarized evidence from human neuroimaging, postmortem, and genetic and pharmacological studies, and put emphasis on the GABAergic synaptic dysregulation and consequent E/I imbalance. We attempt to illuminate the pathophysiological role of structural and functional synaptic dysregulation in ASD and provide insights for future investigation.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Ranji Cui
- *Correspondence: Tongtong Ge, ; Ranji Cui,
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22
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Kanlayaprasit S, Thongkorn S, Panjabud P, Jindatip D, Hu VW, Kikkawa T, Osumi N, Sarachana T. Autism-Related Transcription Factors Underlying the Sex-Specific Effects of Prenatal Bisphenol A Exposure on Transcriptome-Interactome Profiles in the Offspring Prefrontal Cortex. Int J Mol Sci 2021; 22:13201. [PMID: 34947998 PMCID: PMC8708761 DOI: 10.3390/ijms222413201] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/03/2021] [Accepted: 12/05/2021] [Indexed: 11/16/2022] Open
Abstract
Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome-interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring's prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring's prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.
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Grants
- FRB65_hea(80)_175_37_05 Fundamental Fund, Chulalongkorn University
- AHS-CU 61004 Faculty of Allied Health Sciences Research Fund, Chulalongkorn University
- GRU 6300437001-1 Ratchadapisek Somphot Fund for Supporting Research Unit, Chulalongkorn University
- GRU_64_033_37_004 Ratchadapisek Somphot Fund for Supporting Research Unit, Chulalongkorn University
- The 100th Anniversary Chulalongkorn University Fund for Doctoral Scholarship, Graduate School, Chulalongkorn University
- The Overseas Research Experience Scholarship for Graduate Students from Graduate School, Chulalongkorn University
- PHD/0029/2561 The Royal Golden Jubilee Ph.D. Programme Scholarship, Thailand Research Fund and National Research Council of Thailand
- National Research Council of Thailand (NRCT)
- GCUGR1125623067D-67 The 90th Anniversary Chulalongkorn University Fund (Ratchadaphiseksomphot Endowment Fund), Graduate School, Chulalongkorn University
- GCUGR1125632108D-108 The 90th Anniversary Chulalongkorn University Fund (Ratchadaphiseksomphot Endowment Fund), Graduate School, Chulalongkorn University
- 2073011 Chulalongkorn University Laboratory Animal Center (CULAC) Grant
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Affiliation(s)
- Songphon Kanlayaprasit
- The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (S.K.); (S.T.); (P.P.)
| | - Surangrat Thongkorn
- The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (S.K.); (S.T.); (P.P.)
| | - Pawinee Panjabud
- The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (S.K.); (S.T.); (P.P.)
| | - Depicha Jindatip
- Systems Neuroscience of Autism and PSychiatric Disorders (SYNAPS) Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand;
- Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Valerie W. Hu
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA;
| | - Takako Kikkawa
- Department of Developmental Neuroscience, United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Sendai 980-8577, Miyagi, Japan; (T.K.); (N.O.)
| | - Noriko Osumi
- Department of Developmental Neuroscience, United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Sendai 980-8577, Miyagi, Japan; (T.K.); (N.O.)
| | - Tewarit Sarachana
- Systems Neuroscience of Autism and PSychiatric Disorders (SYNAPS) Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand;
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23
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Shafaghi A, Vakili Shahrbabaki SS, Aminzadeh A, Heidari MR, Shamsi Meymandi M, Bashiri H. The effect of early handling on anxiety-like behaviors of rats exposed to valproic acid pre-and post-natally. Neurotoxicol Teratol 2021; 89:107050. [PMID: 34801733 DOI: 10.1016/j.ntt.2021.107050] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 10/23/2021] [Accepted: 11/15/2021] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Autism spectrum disorder (ASD) is a complex, behaviorally defined disorder of the immature brain as a result of genetic and environmental risk factors, such as prenatal exposure to valproic acid (VPA). This syndrome is known for its high prevalence. On the other hand, postnatal manipulations have been shown to affect brain development, cortical neuroscience, and pituitary-adrenal activity. In early handling (EH) procedure, pups are removed from their mother on a daily basis from birth to lactation, are physically touched, and exposed to the (a) new environment. In the present study, the effect of EH on anxiety-like behaviors in rats exposed pre- and post-natally to valproic acid was investigated. METHODS Pregnant Wistar rats were randomly separated into six groups which are prenatal saline, Prenatal VPA, Prenatal VPA + EH and postnatal saline, Postnatal VPA, Postnatal VPA + EH. VPA administration was performed either on ED12.5 (600 mg/kg, i.p.) or PD 2-4 (400 mg/kg, s.c.). In the groups receiving EH, pups underwent physical handling from PD 1 to 21. On postnatal day 21 all offspring were weaned and the behavioral tests were performed on 30 and 31 days of age. Elevated plus maze and open field tests were used to investigate anxiety-like behaviors. RESULTS The results revealed that intraperitoneal injection of valrpoic acid (600 mg.kg) during pregnancy significantly reduced OAT% in males (p < 0.01) and females in a non-significant manner (p > 0.05). In comparison, rearing counts of prenatal VPA groups significantly increased in female sex (p < 0.05) in the EPM test. Following postnatal VPA administration (400 mg/kg), decrease in the time spent in central zone occurred in female rats in the open filed (p < 0.05), as well as a significant increase in the number of grooming of the male sex (p < 0.05). Applying Early Handling to male and female Wistar rats receiving prenatal VPA significantly reversed the OAT% fall (p < 0.05). EH in postnatally VPA exposed animals significantly decreased the OAT% and OAE% criteria, while increasing the locomotor activity of the female sex (p < 0.05). Compared with the postnatal VPA group, no significant change was reported in the EPM performance of postnatal VPA + EH group in neither of sexes (p > 0.05). CONCLUSION The findings of this study suggest that injections of valproic acid during pregnancy lead to anxiety-like behaviors in male offspring, which EH can improve (attenuate) to some extent. VPA injections on the second to the fourth day of infancy did not have a profound effect on anxiety level. Further behavioral studies need to be performed using other devices to investigate anxiety-like behaviors and to determine the mechanisms involved in these behaviors.
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Affiliation(s)
- Abouzar Shafaghi
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyyed Sajjad Vakili Shahrbabaki
- Department of Biology, University of Turku, Turku, Finland; Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Azadeh Aminzadeh
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mahmoud Reza Heidari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran; Pharmaceutical Research Center, Kerman University of Medical Sciences, Kerman, Iran.
| | - Manzumeh Shamsi Meymandi
- Pathology and Stem Cells Research Center, Kerman Medical School, Kerman University of Medical Sciences, Kerman, Iran.; Neuroscience Research Center, Institute of Neuropharmacology, Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran..
| | - Hamideh Bashiri
- Neuroscience Research Center, Institute of Neuropharmacology, Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.; Sirjan Faculty of Medical Science, Sirjan, Iran..
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24
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Sawada K, Kamiya S, Aoki I. The Proliferation of Dentate Gyrus Progenitors in the Ferret Hippocampus by Neonatal Exposure to Valproic Acid. Front Neurosci 2021; 15:736313. [PMID: 34650400 PMCID: PMC8505998 DOI: 10.3389/fnins.2021.736313] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/30/2021] [Indexed: 11/13/2022] Open
Abstract
Prenatal and neonatal exposure to valproic acid (VPA) is associated with human autism spectrum disorder (ASD) and can alter the development of several brain regions, such as the cerebral cortex, cerebellum, and amygdala. Neonatal VPA exposure induces ASD-like behavioral abnormalities in a gyrencephalic mammal, ferret, but it has not been evaluated in brain regions other than the cerebral cortex in this animal. This study aimed to facilitate a comprehensive understanding of brain abnormalities induced by developmental VPA exposure in ferrets. We examined gross structural changes in the hippocampus and tracked proliferative cells by 5-bromo-2-deoxyuridine (BrdU) labeling following VPA administration to ferret infants on postnatal days (PDs) 6 and 7 at 200 μg/g of body weight. Ex vivo short repetition time/time to echo magnetic resonance imaging (MRI) with high spatial resolution at 7-T was obtained from the fixed brain of PD 20 ferrets. The hippocampal volume estimated using MRI-based volumetry was not significantly different between the two groups of ferrets, and optical comparisons on coronal magnetic resonance images revealed no differences in gross structures of the hippocampus between VPA-treated and control ferrets. BrdU-labeled cells were observed throughout the hippocampus of both two groups at PD 20. BrdU-labeled cells were immunopositive for Sox2 (>70%) and almost immunonegative for NeuN, S100 protein, and glial fibrillary acidic protein. BrdU-labeled Sox2-positive progenitors were abundant, particularly in the subgranular layer of the dentate gyrus (DG), and were denser in VPA-treated ferrets. When BrdU-labeled Sox2-positive progenitors were examined at 2 h after the second VPA administration on PD 7, their density in the granular/subgranular layer and hilus of the DG was significantly greater in VPA-treated ferrets compared to controls. The findings suggest that VPA exposure to ferret infants facilitates the proliferation of DG progenitors, supplying excessive progenitors for hippocampal adult neurogenesis to the subgranular layer.
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Affiliation(s)
- Kazuhiko Sawada
- Department of Nutrition, Faculty of Medical and Health Sciences, Tsukuba International University, Tsuchiura, Japan
| | - Shiori Kamiya
- Department of Nutrition, Faculty of Medical and Health Sciences, Tsukuba International University, Tsuchiura, Japan
| | - Ichio Aoki
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba, Japan.,Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba, Japan
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25
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Bassetti D, Luhmann HJ, Kirischuk S. Presynaptic GABA B receptor-mediated network excitation in the medial prefrontal cortex of Tsc2 +/- mice. Pflugers Arch 2021; 473:1261-1271. [PMID: 34279736 PMCID: PMC8302497 DOI: 10.1007/s00424-021-02576-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/21/2021] [Accepted: 05/05/2021] [Indexed: 11/02/2022]
Abstract
The TSC1 and TSC2 tumor suppressor genes control the activity of mechanistic target of rapamycin (mTOR) pathway. Elevated activity of this pathway in Tsc2+/- mouse model leads to reduction of postsynaptic GABAB receptor-mediated inhibition and hyperexcitability in the medial prefrontal cortex (mPFC). In this study, we asked whether presynaptic GABAB receptors (GABABRs) can compensate this shift of hyperexcitability. Experiments were performed in brain slices from adolescent wild-type (WT) and Tsc2+/- mice. Miniature and spontaneous postsynaptic currents (m/sPSCs) were recorded from layer 2/3 pyramidal neurons in mPFC using patch-clamp technique using a Cs+-based intrapipette solution. Presynaptic GABABRs were activated by baclofen (10 µM) or blocked by CGP55845 (1 µM). Independent on genotype, GABABR modulators bidirectionally change miniature excitatory postsynaptic current (mEPSC) frequency by about 10%, indicating presynaptic GABABR-mediated effects on glutamatergic transmission are comparable in both genotypes. In contrast, frequencies of both mIPSCs and sIPCSs were suppressed by baclofen stronger in Tsc2+/- neurons than in WT ones, whereas CGP55845 significantly increased (m/s)IPSC frequencies only in WT cells. Effects of baclofen and CGP55845 on the amplitudes of evoked (e)IPSCs confirmed these observations. These data indicate (1) that GABAergic synapses are inhibited by ambient GABA in WT but not in Tsc2+/- slices, and (2) that baclofen shifts the E/I ratio, determined as the ratio of (m/s)EPSC frequency to (m/s)IPSC frequency, towards excitation only in Tsc2+/- cells. This excitatory presynaptic GABABR-mediated action has to be taken into account for a possible medication of mental disorders using baclofen.
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Affiliation(s)
- Davide Bassetti
- Institute of Physiology, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128, Mainz, Germany.
| | - Heiko J Luhmann
- Institute of Physiology, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128, Mainz, Germany
| | - Sergei Kirischuk
- Institute of Physiology, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128, Mainz, Germany
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26
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Thornton AM, Humphrey RM, Kerr DM, Finn DP, Roche M. Increasing Endocannabinoid Tone Alters Anxiety-Like and Stress Coping Behaviour in Female Rats Prenatally Exposed to Valproic Acid. Molecules 2021; 26:molecules26123720. [PMID: 34207178 PMCID: PMC8233839 DOI: 10.3390/molecules26123720] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 12/13/2022] Open
Abstract
Given the sex differences evident in the prevalence of autism, there is an increased awareness of the importance of including females in autism research to determine sexual dimorphism and sex-specific treatments. Cannabinoids and endocannabinoid modulators have been proposed as potential novel treatments for autism-related symptoms; however, few studies to date have examined if these pharmacological agents elicit sex-specific effects. The aim of the present study was to use the valproic acid (VPA) model of autism to compare the behavioural responses of male and female rats and examine the effects of increasing endocannabinoid tone on the behavioural responses of VPA-exposed female rats. These data revealed that VPA-exposed male, but not female, rats exhibit reduced social responding in the three-chamber and olfactory habituation/dishabituation (OHD) test during adolescence. In comparison, VPA-exposed female, but not male, adolescent rats exhibited anxiety-like behaviour in the elevated plus maze (EPM) and open field test (OFT). In VPA-exposed female rats, increasing 2-AG levels augmented anxiety-like behaviour in the EPM and OFT, while increasing AEA levels reduced stress coping behaviour in the swim stress test. These data highlight sexual dimorphic behaviours in the VPA model and indicate that enhancing endocannabinoid levels may exacerbate negative affective behaviour in VPA-exposed females. Thus, considerations should be paid to the possible sex-specific effects of cannabinoids for the treatment of symptoms associated with autism.
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Affiliation(s)
- Aoife M. Thornton
- Physiology, School of Medicine, National University of Ireland Galway, H91 W5P7 Galway, Ireland; (A.M.T.); (R.M.H.)
- Galway Neuroscience Centre, National University of Ireland Galway, H91 W5P7 Galway, Ireland;
| | - Rachel M. Humphrey
- Physiology, School of Medicine, National University of Ireland Galway, H91 W5P7 Galway, Ireland; (A.M.T.); (R.M.H.)
- Galway Neuroscience Centre, National University of Ireland Galway, H91 W5P7 Galway, Ireland;
- Centre for Pain Research, National University of Ireland Galway, H91 W5P7 Galway, Ireland
| | - Daniel M. Kerr
- Pharmacology and Therapeutics, School of Medicine, National University of Ireland Galway, H91 W5P7 Galway, Ireland;
| | - David P. Finn
- Galway Neuroscience Centre, National University of Ireland Galway, H91 W5P7 Galway, Ireland;
- Centre for Pain Research, National University of Ireland Galway, H91 W5P7 Galway, Ireland
- Pharmacology and Therapeutics, School of Medicine, National University of Ireland Galway, H91 W5P7 Galway, Ireland;
| | - Michelle Roche
- Physiology, School of Medicine, National University of Ireland Galway, H91 W5P7 Galway, Ireland; (A.M.T.); (R.M.H.)
- Galway Neuroscience Centre, National University of Ireland Galway, H91 W5P7 Galway, Ireland;
- Centre for Pain Research, National University of Ireland Galway, H91 W5P7 Galway, Ireland
- Correspondence:
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27
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Timing and Intertemporal Choice Behavior in the Valproic Acid Rat Model of Autism Spectrum Disorder. J Autism Dev Disord 2021; 52:2414-2429. [DOI: 10.1007/s10803-021-05129-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2021] [Indexed: 12/16/2022]
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28
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Adjimann TS, Argañaraz CV, Soiza-Reilly M. Serotonin-related rodent models of early-life exposure relevant for neurodevelopmental vulnerability to psychiatric disorders. Transl Psychiatry 2021; 11:280. [PMID: 33976122 PMCID: PMC8113523 DOI: 10.1038/s41398-021-01388-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 04/16/2021] [Accepted: 04/21/2021] [Indexed: 01/22/2023] Open
Abstract
Mental disorders including depression and anxiety are continuously rising their prevalence across the globe. Early-life experience of individuals emerges as a main risk factor contributing to the developmental vulnerability to psychiatric disorders. That is, perturbing environmental conditions during neurodevelopmental stages can have detrimental effects on adult mood and emotional responses. However, the possible maladaptive neural mechanisms contributing to such psychopathological phenomenon still remain poorly understood. In this review, we explore preclinical rodent models of developmental vulnerability to psychiatric disorders, focusing on the impact of early-life environmental perturbations on behavioral aspects relevant to stress-related and psychiatric disorders. We limit our analysis to well-established models in which alterations in the serotonin (5-HT) system appear to have a crucial role in the pathophysiological mechanisms. We analyze long-term behavioral outcomes produced by early-life exposures to stress and psychotropic drugs such as the selective 5-HT reuptake inhibitor (SSRI) antidepressants or the anticonvulsant valproic acid (VPA). We perform a comparative analysis, identifying differences and commonalities in the behavioral effects produced in these models. Furthermore, this review discusses recent advances on neurodevelopmental substrates engaged in these behavioral effects, emphasizing the possible existence of maladaptive mechanisms that could be shared by the different models.
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Affiliation(s)
- Tamara S. Adjimann
- grid.7345.50000 0001 0056 1981Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carla V. Argañaraz
- grid.7345.50000 0001 0056 1981Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Mariano Soiza-Reilly
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
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29
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Gruenbaum BF, Sandhu MRS, Bertasi RAO, Bertasi TGO, Schonwald A, Kurup A, Gruenbaum SE, Freedman IG, Funaro MC, Blumenfeld H, Sanacora G. Absence seizures and their relationship to depression and anxiety: Evidence for bidirectionality. Epilepsia 2021; 62:1041-1056. [PMID: 33751566 PMCID: PMC8443164 DOI: 10.1111/epi.16862] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/12/2022]
Abstract
Absence seizures (AS), presenting as short losses of consciousness with staring spells, are a common manifestation of childhood epilepsy that is associated with behavioral, emotional, and social impairments. It has also been suggested that patients with AS are more likely to suffer from mood disorders such as depression and anxiety. This systematic review and meta-analysis synthesizes human and animal models that investigated mood disorders and AS. Of the 1019 scientific publications identified, 35 articles met the inclusion criteria for this review. We found that patients with AS had greater odds of developing depression and anxiety when compared to controls (odds ratio = 4.93, 95% confidence interval = 2.91-8.35, p < .01). The included studies further suggest a strong correlation between AS and depression and anxiety in the form of a bidirectional relationship. The current literature emphasizes that these conditions likely share underlying mechanisms, such as genetic predisposition, neurophysiology, and anatomical pathways. Further research will clarify this relationship and ensure more effective treatment for AS and mood disorders.
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Affiliation(s)
- Benjamin F Gruenbaum
- Department of Anesthesiology, Yale School of Medicine, New Haven, Connecticut, USA.,Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, Florida, USA
| | - Mani Ratnesh S Sandhu
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Raphael A O Bertasi
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, Florida, USA
| | - Tais G O Bertasi
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, Florida, USA
| | - Antonia Schonwald
- Department of Anesthesiology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Anirudh Kurup
- Department of Anesthesiology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Shaun E Gruenbaum
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, Florida, USA
| | - Isaac G Freedman
- Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Melissa C Funaro
- Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, Connecticut, USA
| | - Hal Blumenfeld
- Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA.,Department of Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.,Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA
| | - Gerard Sanacora
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
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Wang K, Li N, Xu M, Huang M, Huang F. Glyoxalase 1 Inhibitor Alleviates Autism-like Phenotype in a Prenatal Valproic Acid-Induced Mouse Model. ACS Chem Neurosci 2020; 11:3786-3792. [PMID: 33166134 DOI: 10.1021/acschemneuro.0c00482] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Autism spectrum disorder (ASD) is a severe neurological and developmental disorder that impairs a person's ability to socialize and communicate and affects behavior. The number of patients diagnosed with ASD has risen rapidly. However, the pathophysiology of ASD is poorly understood, and drugs for ASD treatment are strikingly limited. This study aims to evaluate the roles of glyoxalase 1 (GLO1)-methylglyoxal (MG)-γ-aminobutyric acid (GABA) signaling in ASD using a valproic acid (VPA)-induced animal model of autism. The GLO1 levels were analyzed by RT-qPCR and Western blot assay, and MG levels were measured with a Methylglyoxal Assay Kit. The open-field and sniff duration tests were used to assess the interest and anxiety of VPA mice. The three-chamber, marble-burying, and tail-flick tests were applied to determine the sociability, repetitive behavior, and nociceptive threshold of VPA mice. Our results demonstrated that increased GLO1 and decreased MG were observed in VPA mice. Administration of S-p-bromobenzylglutathione cyclopentyl diester (BrBzGCp2), a GLO1 inhibitor, was beneficial for alleviating anxiety, reducing repetitive behavior, and improving the impaired sociability and nociceptive threshold of VPA mice. BrBzGCp2 treatment may be developed as a promising therapeutic strategy for patients with ASD.
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Affiliation(s)
- Kui Wang
- Psychiatric Ward, Qingdao Mental Health Center, Qingdao University, No 299 Nanjing Road, Qingdao, 266034 Shandong, China
| | - Na Li
- Psychiatric Ward, Qingdao Mental Health Center, Qingdao University, No 299 Nanjing Road, Qingdao, 266034 Shandong, China
| | - Min Xu
- Psychiatric Ward, Qingdao Mental Health Center, Qingdao University, No 299 Nanjing Road, Qingdao, 266034 Shandong, China
| | - Meng Huang
- Department of Laboratory Medicine, Lao-shan Disease Area, the Affiliated Hospital of Qingdao University, Qingdao, 266000 Shandong, China
| | - Fei Huang
- Psychiatric Ward, Qingdao Mental Health Center, Qingdao University, No 299 Nanjing Road, Qingdao, 266034 Shandong, China
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Mansour Y, Ahmed SN, Kulesza R. Abnormal morphology and subcortical projections to the medial geniculate in an animal model of autism. Exp Brain Res 2020; 239:381-400. [PMID: 33200290 DOI: 10.1007/s00221-020-05982-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 11/04/2020] [Indexed: 12/21/2022]
Abstract
Auditory dysfunction, including hypersensitivity and tinnitus, is a common symptom of autism spectrum disorder (ASD). Prenatal exposure to the antiseizure medication valproic acid (VPA) significantly increases the risk of ASD in humans and similar exposure is utilized as an animal model of ASD in rodents. Animals exposed to VPA in utero have abnormal activity in their auditory cortex in response to sounds, fewer neurons, abnormal neuronal morphology, reduced expression of calcium-binding proteins, and reduced ascending projections to the central nucleus of the inferior colliculus. Unfortunately, these previous studies of central auditory circuits neglect the medial geniculate (MG), which serves as an important auditory relay from the midbrain to the auditory cortex. Here, we examine the structure and connectivity of the medial geniculate (MG) in rats prenatally exposed to VPA. Our results indicate that VPA exposure results in significantly smaller and fewer neurons in the ventral and medial nuclei of the MG. Furthermore, injections of the retrograde tract tracer fluorogold (FG) in the MG result in significantly fewer FG+ neurons in the inferior colliculus, superior olivary complex, and ventral cochlear nucleus. Together, we interpret these findings to indicate that VPA exposure results in hypoplasia throughout the auditory circuits and that VPA has a differential impact on some long-range axonal projections from brainstem centers to the thalamus. Together, our findings support the widespread impact of VPA on neurons and sensory circuits in the developing brain.
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Affiliation(s)
- Yusra Mansour
- Department of Anatomy, Lake Erie College of Osteopathic Medicine, 1858 West Grandview Blvd, Erie, PA, 16504, USA
| | - Syed Naved Ahmed
- Department of Anatomy, Lake Erie College of Osteopathic Medicine, 1858 West Grandview Blvd, Erie, PA, 16504, USA
| | - Randy Kulesza
- Department of Anatomy, Lake Erie College of Osteopathic Medicine, 1858 West Grandview Blvd, Erie, PA, 16504, USA.
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McKinnell ZE, Maze T, Ramos A, Challans B, Plakke B. Valproic acid treated female Long-Evans rats are impaired on attentional set-shifting. Behav Brain Res 2020; 397:112966. [PMID: 33053383 DOI: 10.1016/j.bbr.2020.112966] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 08/26/2020] [Accepted: 10/07/2020] [Indexed: 01/14/2023]
Abstract
Autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by social deficits, communication impairments, restrictive behaviors, and cognitive flexibility deficits. The valproic acid (VPA) model of autism has been widely used to examine changes in rodent behavior and neurobiology to better understand ASD. This study examined social and anxiety behavior as well as cognitive flexibility in VPA and control offspring. Results for social behavior were consistent with prior studies showing reduced sociability in VPA rats and increased self-grooming, which may be viewed as a repetitive behavior. VPA rats also had deficits in performing the set-shifting task, with female VPA rats demonstrating greater impairment compared to female control rats and male VPA rats. These results support the hypothesis that females diagnosed with ASD may suffer from different symptoms and present a unique behavioral profile compared to males with ASD. Female VPA rats were also less likely to form an attentional set; offering evidence that the VPA model of autism is encompassing executive function deficits similar to those observed in humans with ASD.
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Affiliation(s)
- Zach E McKinnell
- Department of Psychological Sciences, Kansas State University, Manhattan, KS, 66506, USA
| | - Tessa Maze
- Department of Psychological Sciences, Kansas State University, Manhattan, KS, 66506, USA
| | - Alejandro Ramos
- Department of Psychological Sciences, Kansas State University, Manhattan, KS, 66506, USA
| | - Brandon Challans
- Department of Psychological Sciences, Kansas State University, Manhattan, KS, 66506, USA
| | - Bethany Plakke
- Department of Psychological Sciences, Kansas State University, Manhattan, KS, 66506, USA.
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Chaliha D, Albrecht M, Vaccarezza M, Takechi R, Lam V, Al-Salami H, Mamo J. A Systematic Review of the Valproic-Acid-Induced Rodent Model of Autism. Dev Neurosci 2020; 42:12-48. [DOI: 10.1159/000509109] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 06/02/2020] [Indexed: 11/19/2022] Open
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Shamsi Meymandi M, Sepehri G, Moslemizadeh A, Vakili Shahrbabaki S, Bashiri H. Prenatal pregabalin is associated with sex-dependent alterations in some behavioral parameters in valproic acid-induced autism in rat offspring. Int J Dev Neurosci 2020; 80:500-511. [PMID: 32588482 DOI: 10.1002/jdn.10046] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/10/2020] [Accepted: 06/15/2020] [Indexed: 11/10/2022] Open
Abstract
This study was performed to evaluate the effects of prenatal exposure to pregabalin (PGB) on behavioral changes of rat offspring in an animal model of valproic acid (VPA)-induced autism-like symptoms. Pregnant rats received VPA (600 mg/kg/i.p.) once at 12.5 gestational days for autism-like symptom induction in offspring. After the delivery single male and single female offspring from each mother were randomly selected for behavioral test (anxiety, pain response, pleasure, and motor function) at 60th day adulthood (n = 7). Offspring received prenatal PGB (15 & 30 mg/kg/i.p.) during gestational days 9.5 to 15.5 either alone or in combination with VPA (PGB15, PGB30, PGB15 + VPA, and PGB30 + VPA). Control offspring received normal saline during the same period. The result showed that prenatal VPA exposure was associated with autism-like behaviors in rat offspring. PGB treatment during the gestational period revealed significant reduction in sucrose preference test and anxiety in elevated plus maze and open field test in offspring. Also, PGB treatments exhibited a dose-dependent increase in pain threshold in prenatally VPA exposed rats in tail-flick and hot plate test. Also, there was a sex-related significant impairment in motor function in beam balance and open field test, and male rats were affected more than females. However, no significant sex differences in sucrose preference and pain sensitivity were observed in prenatal PGB-treated rat offspring. In conclusion, prenatal exposure to VPA increased the risk of autism-like behaviors in the offspring rats, and PGB treatment during the gestational period was associated with some beneficial effects, including anxiety reduction and motor impairment in autism-like symptoms in rat offspring.
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Affiliation(s)
- Manzumeh Shamsi Meymandi
- Pathology and Stem Cells Research Center, Kerman Medical School, Kerman University of Medical Sciences, Kerman, Iran.,Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Gholamreza Sepehri
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | | | | | - Hamideh Bashiri
- Physiology Research Center, Department of Physiology and Pharmacology, Medical School, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.,Department of Physiology and Pharmacology, Sirjan School of Medical Sciences, Sirjan, Iran
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Sex dependent alterations of resveratrol on social behaviors and nociceptive reactivity in VPA-induced autistic-like model in rats. Neurotoxicol Teratol 2020; 81:106905. [PMID: 32534151 DOI: 10.1016/j.ntt.2020.106905] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 06/01/2020] [Accepted: 06/08/2020] [Indexed: 01/20/2023]
Abstract
INTRODUCTION The present study was designed to clarify the effects of resveratrol (RSV) on social behavioral alterations and nociceptive reactivity in valproic acid (VPA)-induced autistic-like model in female and male rats. METHODS Pregnant Wistar rats were randomly divided in five groups. Animals received saline, DMSO, VPA, RSV and RSV + VPA. VPA was administered (600 mg/kg, i. p.) on embryonic day 12.5 (E12.5) and pretreatment by resveratrol (3.6 mg/kg, s. c.) was applied on E6.5 until E18.5. All offspring were weaned on postnatal day 21 and the experiments were done in male and female rats on day 60. Social interaction, hot plate and tail flick tests were set out to assess social deficits and pain threshold, respectively. Sociability index (SI), Social novelty index (SNI) and latency time were calculated as the standard indices of social behaviors and pain threshold, respectively. RESULTS The results indicated that systemic intraperitoneal administration of VPA (600 mg/kg) significantly decreased SI and SNI in social interaction test (SIT) especially in male rats, indicating the social impairments caused by VPA. RSV (3.6 mg/kg, s. c.) reversed VPA-induced social deficits in male rats, but not in female group. VPA administration resulted in significant increase in latency time in the hot plate and tail flick tests in male rats, whereas it had no such dramatic effect in females. RSV administration in combination with VPA had no significant effect on latency time compared to the valproic acid group in male rats. It is important to note that RSV by itself had no significant effect on SI, SNI and latency time in female and male rats. CONCLUSION It can be concluded that valproic acid produces autistic-like behaviors and increases pain threshold in male rats which may be ameliorated at least in part by resveratrol administration. Further studies are needed to elucidate the molecular mechanisms involved in valproic acid and resveratrol-induced effects.
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Lefter R, Ciobica A, Antioch I, Ababei DC, Hritcu L, Luca AC. Oxytocin Differentiated Effects According to the Administration Route in a Prenatal Valproic Acid-Induced Rat Model of Autism. ACTA ACUST UNITED AC 2020; 56:medicina56060267. [PMID: 32485966 PMCID: PMC7353871 DOI: 10.3390/medicina56060267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/14/2020] [Accepted: 05/25/2020] [Indexed: 12/31/2022]
Abstract
Background and objectives: The hormone oxytocin (OXT) has already been reported in both human and animal studies for its promising therapeutic potential in autism spectrum disorder (ASD), but the comparative effectiveness of various administration routes, whether central or peripheral has been insufficiently studied. In the present study, we examined the effects of intranasal (IN) vs. intraperitoneal (IP) oxytocin in a valproic-acid (VPA) autistic rat model, focusing on cognitive and mood behavioral disturbances, gastrointestinal transit and central oxidative stress status. Materials and Methods: VPA prenatally-exposed rats (500 mg/kg; age 90 days) in small groups of 5 (n = 20 total) were given OXT by IP injection (10 mg/kg) for 8 days consecutively or by an adapted IN pipetting protocol (12 IU/kg, 20 μL/day) for 4 consecutive days. Behavioral tests were performed during the last three days of OXT treatment, and OXT was administrated 20 minutes before each behavioral testing for each rat. Biochemical determination of oxidative stress markers in the temporal area included superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). A brief quantitative assessment of fecal discharge over a period of 24 hours was performed at the end of the OXT treatment to determine differences in intestinal transit. Results: OXT improved behavioral and oxidative stress status in both routes of administration, but IN treatment had significantly better outcome in improving short-term memory, alleviating depressive manifestations and mitigating lipid peroxidation in the temporal lobes. Significant correlations were also found between behavioral parameters and oxidative stress status in rats after OXT administration. The quantitative evaluation of the gastrointestinal (GI) transit indicated lower fecal pellet counts in the VPA group and homogenous average values for the control and both OXT treated groups. Conclusions: The data from the present study suggest OXT IN administration to be more efficient than IP injections in alleviating autistic cognitive and mood dysfunctions in a VPA-induced rat model. OXT effects on the cognitive and mood behavior of autistic rats may be associated with its effects on oxidative stress. Additionally, present results provide preliminary evidence that OXT may have a balancing effect on gastrointestinal motility.
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Affiliation(s)
- Radu Lefter
- Center of Biomedical Research, Romanian Academy, B dul Carol I, No 8, 700505 Iasi, Romania;
| | - Alin Ciobica
- Department of Research, Faculty of Biology, Alexandru Ioan Cuza University, B dul Carol I, No 11, 700506 Iasi, Romania;
- Correspondence: (A.C.); (L.H.)
| | - Iulia Antioch
- Department of Research, Faculty of Biology, Alexandru Ioan Cuza University, B dul Carol I, No 11, 700506 Iasi, Romania;
| | - Daniela Carmen Ababei
- “Grigore T.Popa” University of Medicine and Pharmacy, 16, Universitatii Street, 700115 Iasi, Romania; (D.C.A.); (A.-C.L.)
| | - Luminita Hritcu
- Faculty of Veterinary Medicine, University of Agricultural Sciencies and Veterinary Medicine “Ion Ionescu de la Brad” of Iasi, 3rd Mihail Sadoveanu Alley, 700490 Iasi, Romania
- Correspondence: (A.C.); (L.H.)
| | - Alina-Costina Luca
- “Grigore T.Popa” University of Medicine and Pharmacy, 16, Universitatii Street, 700115 Iasi, Romania; (D.C.A.); (A.-C.L.)
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In utero exposure to valproic acid disrupts ascending projections to the central nucleus of the inferior colliculus from the auditory brainstem. Exp Brain Res 2020; 238:551-563. [DOI: 10.1007/s00221-020-05729-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 01/07/2020] [Indexed: 12/11/2022]
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38
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Wu HF, Lu TY, Chu MC, Chen PS, Lee CW, Lin HC. Targeting the inhibition of fatty acid amide hydrolase ameliorate the endocannabinoid-mediated synaptic dysfunction in a valproic acid-induced rat model of Autism. Neuropharmacology 2020; 162:107736. [DOI: 10.1016/j.neuropharm.2019.107736] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 08/02/2019] [Accepted: 08/05/2019] [Indexed: 10/26/2022]
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Gao X, Zheng R, Ma X, Gong Z, Xia D, Zhou Q. Elevated Level of PKMζ Underlies the Excessive Anxiety in an Autism Model. Front Mol Neurosci 2019; 12:291. [PMID: 31849605 PMCID: PMC6893886 DOI: 10.3389/fnmol.2019.00291] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/13/2019] [Indexed: 12/14/2022] Open
Abstract
Anxiety affects the life quality of a significant percentage of autism patients. To understand the possible biological basis of this high anxiety level, we used a valproic acid (VPA) model of autism. Anxiety level is significantly higher in VPA-injected mice, at both P35 and P70. In addition, protein kinase Mζ (PKMζ) level in the basolateral amygdala (BLA) is significantly higher in VPA mice at both ages. Consistent with this finding, infusion of a PKMζ-blocking peptide z-pseudosubstrate inhibitory peptide (ZIP) into BLA significantly reduced anxiety levels in VPA mice. Furthermore, viral overexpression of PKMζ in the BLA led to elevated anxiety level in Wild Type (WT) mice, with concomitant higher intrinsic excitability of BLA excitatory neurons. Altogether, our results indicate a key contribution of BLA PKMζ level to anxiety, especially in autism; and this finding may provide a further understanding of the pathogenesis as well as treatment of anxiety symptoms in autism patients.
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Affiliation(s)
- Xiaoli Gao
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Rui Zheng
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Xiaoyan Ma
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Zhiting Gong
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.,Department of Anatomy, College of Preclinical Medicine, Dali University, Dali, China
| | - Dan Xia
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.,Department of Child Healthcare, Shenzhen Children's Hospital, Shenzhen, China
| | - Qiang Zhou
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.,State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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Mirza R, Sharma B. Benefits of Fenofibrate in prenatal valproic acid-induced autism spectrum disorder related phenotype in rats. Brain Res Bull 2019; 147:36-46. [PMID: 30769127 DOI: 10.1016/j.brainresbull.2019.02.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 01/29/2019] [Accepted: 02/06/2019] [Indexed: 12/12/2022]
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with two major behavioral symptoms i.e. repetitive behavior and social-communication impairment. The unknown etiology of ASD is responsible for the difficulty in identifying the possible therapeutic modulators for ASD. Valproic acid (VPA) is an anticonvulsant drug in both human and rodents with teratogenic effects during pregnancy. Therefore, prenatal exposure of VPA induced autism spectrum disorder like phenotypes in both human and rodents. Peroxisome proliferator-activated receptor-alpha (PPAR-α) is widely localized in the brain. This research investigates the utility of fenofibrate, a selective agonist of PPAR-α in prenatal VPA-induced experimental ASD in Wistar rats. The prenatal VPA has induced social impairment (three chambers social behavior apparatus), repetitive behavior (Y-maze), hyperlocomotion (actophotometer), anxiety (elevated plus maze) and low exploratory activity (hole board test). Also, prenatal VPA treated rats have shown higher levels of oxidative stress (increased in thiobarbituric acid reactive species and decreased in reduced glutathione level) and inflammation (increased in interleukin-6, tumor necrosis factor-α and decreased in interleukin-10) in the cerebellum, brainstem and prefrontal cortex. Treatment with fenofibrate significantly attenuated prenatal VPA-induced social impairment, repetitive behavior, hyperactivity, anxiety, and low exploratory activity. Furthermore, fenofibrate also decreased the prenatal VPA-induced oxidative stress and inflammation in brain regions. Hence, it may be concluded that fenofibrate may provide neurobehavioral and biochemical benefits in prenatal VPA-induced autism phenotypes in rats.
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Affiliation(s)
- Roohi Mirza
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, India
| | - Bhupesh Sharma
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, India; CNS Pharmacology, Conscience Research, Delhi, India.
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Wang R, Tan J, Guo J, Zheng Y, Han Q, So KF, Yu J, Zhang L. Aberrant Development and Synaptic Transmission of Cerebellar Cortex in a VPA Induced Mouse Autism Model. Front Cell Neurosci 2018; 12:500. [PMID: 30622458 PMCID: PMC6308145 DOI: 10.3389/fncel.2018.00500] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 12/03/2018] [Indexed: 01/27/2023] Open
Abstract
Autistic spectral disorder (ASD) is a prevalent neurodevelopmental disease that affects multiple brain regions. Both clinical and animal studies have revealed the possible involvement of the cerebellum in ASD pathology. In this study, we generated a rodent ASD model through a single prenatal administration of valproic acid (VPA) into pregnant mice, followed by cerebellar morphological and functional studies of the offspring. Behavioral studies showed that VPA exposure led to retardation of critical motor reflexes in juveniles and impaired learning in a tone-conditioned complex motor task in adults. These behavioral phenotypes were associated with premature migration and excess apoptosis of the granular cell (GC) precursor in the cerebellar cortex during the early postnatal period, and the decreased cell density and impaired dendritic arborization of the Purkinje neurons. On acute cerebellar slices, suppressed synaptic transmission of the Purkinje cells were reported in the VPA-treated mice. In summary, converging evidence from anatomical, electrophysiological and behavioral abnormalities in the VPA-treated mice suggest cerebellar pathology in ASD and indicate the potential values of motor dysfunction in the early diagnosis of ASD.
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Affiliation(s)
- Ruanna Wang
- Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Jiahui Tan
- Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Junxiu Guo
- Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Yuhan Zheng
- Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Qing Han
- Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Kwok-Fai So
- Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Jiandong Yu
- Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Li Zhang
- Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
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Wang X, Tao J, Qiao Y, Luo S, Zhao Z, Gao Y, Guo J, Kong J, Chen C, Ge L, Zhang B, Guo P, Liu L, Song Y. Gastrodin Rescues Autistic-Like Phenotypes in Valproic Acid-Induced Animal Model. Front Neurol 2018; 9:1052. [PMID: 30581411 PMCID: PMC6293267 DOI: 10.3389/fneur.2018.01052] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/20/2018] [Indexed: 12/13/2022] Open
Abstract
Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized by impaired social interaction, restricted/repetitive behavior, and anxiety. GABAergic dysfunction has been postulated to underlie these autistic symptoms. Gastrodin is widely used clinically in the treatment of neurological disorders and showed to modulate GABAergic signaling in the animal brain. The present study aimed to determine whether treatment with gastrodin can rescue valproic acid (VPA) induced autistic-like phenotypes, and to determine its possible mechanism of action. Our results showed that administration of gastrodin effectively alleviated the autistic-associated behavioral abnormalities as reflected by an increase in social interaction and decrement in repetitive/stereotyped behavior and anxiety in mice as compared to those in untreated animals. Remarkably, the amelioration in autistic-like phenotypes was accompanied by the restoration of inhibitory synaptic transmission, α5 GABAA receptor, and type 1 GABA transporter (GAT1) expression in the basolateral amygdala (BLA) of VPA-treated mice. These findings indicate that gastrodin may alleviate the autistic symptoms caused by VPA through regulating GABAergic synaptic transmission, suggesting that gastrodin may be a potential therapeutic target in autism.
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Affiliation(s)
- Xiaona Wang
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Jing Tao
- Department of Pathology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Yidan Qiao
- Department of Pathology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Shuying Luo
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Zhenqin Zhao
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Yinbo Gao
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Jisheng Guo
- Center for Translational Medicine, The Sixth People's Hospital of Zhengzhou, Zhengzhou, China
| | - Jinghui Kong
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Chongfen Chen
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Lili Ge
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Bo Zhang
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Pengbo Guo
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Lei Liu
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Yinsen Song
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
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Wang R, Hausknecht K, Shen RY, Haj-Dahmane S. Potentiation of Glutamatergic Synaptic Transmission Onto Dorsal Raphe Serotonergic Neurons in the Valproic Acid Model of Autism. Front Pharmacol 2018; 9:1185. [PMID: 30459605 PMCID: PMC6232663 DOI: 10.3389/fphar.2018.01185] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 09/28/2018] [Indexed: 11/17/2022] Open
Abstract
Autism spectrum disorder (ASD) is characterized by social and communicative impairments and increased repetitive behaviors. These symptoms are often comorbid with increased anxiety. Prenatal exposure to valproic acid (VPA), an anti-seizure and mood stabilizer medication, is a major environmental risk factor of ASD. Given the important role of the serotonergic (5-HT) system in anxiety, we examined the impact of prenatal VPA exposure on the function of dorsal raphe nucleus (DRn) 5-HT neurons. We found that male rats prenatally exposed to VPA exhibited increased anxiety-like behaviors revealed by a decreased time spent on the open arms of the elevated plus maze. Prenatal VPA exposed rats also exhibited a stereotypic behavior as indicated by excessive self-grooming in a novel environment. These behavioral phenotypes were associated with increased electrical activity of putative DRn 5-HT neurons recorded in vitro. Examination of underlying mechanisms revealed that prenatal VPA exposure increased excitation/inhibition ratio in synapses onto these neurons. The effect was mainly mediated by enhanced glutamate but not GABA release. We found reduced paired-pulse ratio (PPR) of evoked excitatory postsynaptic currents (EPSCs) and increased frequency but not amplitude of miniature EPSCs in VPA exposed rats. On the other hand, presynaptic GABA release did not change in VPA exposed rats, as the PPR of evoked inhibitory postsynaptic currents was unaltered. Furthermore, the spike-timing-dependent long-term potentiation at the glutamatergic synapses was occluded, indicating glutamatergic synaptic transmission is maximized. Lastly, VPA exposure did not alter the intrinsic membrane properties of DRn 5-HT neurons. Taken together, these results indicate that prenatal VPA exposure profoundly enhances glutamatergic synaptic transmission in the DRn and increases spontaneous firing in DRn 5-HT neurons, which could lead to increased serotonergic tone and underlie the increased anxiety and stereotypy after prenatal VPA exposure.
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Affiliation(s)
- Ruixiang Wang
- Research Institute on Addictions, University at Buffalo, The State University of New York, Buffalo, NY, United States.,Department of Psychology, University at Buffalo, The State University of New York, Buffalo, NY, United States
| | - Kathryn Hausknecht
- Research Institute on Addictions, University at Buffalo, The State University of New York, Buffalo, NY, United States
| | - Roh-Yu Shen
- Research Institute on Addictions, University at Buffalo, The State University of New York, Buffalo, NY, United States.,Department of Pharmacology and Toxicology, The Jacob School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States.,Neuroscience Program, University at Buffalo, The State University of New York, Buffalo, NY, United States
| | - Samir Haj-Dahmane
- Research Institute on Addictions, University at Buffalo, The State University of New York, Buffalo, NY, United States.,Department of Pharmacology and Toxicology, The Jacob School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States.,Neuroscience Program, University at Buffalo, The State University of New York, Buffalo, NY, United States
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44
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Dai YC, Zhang HF, Schön M, Böckers TM, Han SP, Han JS, Zhang R. Neonatal Oxytocin Treatment Ameliorates Autistic-Like Behaviors and Oxytocin Deficiency in Valproic Acid-Induced Rat Model of Autism. Front Cell Neurosci 2018; 12:355. [PMID: 30356897 PMCID: PMC6190900 DOI: 10.3389/fncel.2018.00355] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 09/20/2018] [Indexed: 12/22/2022] Open
Abstract
Autism spectrum disorder (ASD) is characterized by impaired social communication and repetitive/stereotyped behaviors. The neuropeptide oxytocin (OXT) plays a critical role in regulating social behaviors in the central nervous system, as indicated in both human and animal studies. We hypothesized that central OXT deficit is one of causes of etiology of ASD, which may be responsible for the social impairments. To test our hypothesis, central OXT system was examined in valproic acid (VPA)-induced rat model of autism (VPA rat). Our results showed that adolescent VPA rats exhibited a lower level of OXT mRNA and fewer OXT-ir cells in the hypothalamus than control rats. Additionally, OXT concentration in cerebrospinal fluid (CSF) was reduced. The number of OXT-ir cells in the supraoptic nucleus (SON) of neonatal VPA rats was also lower. Autistic-like behaviors were observed in these animals as well. We found that an acute intranasal administration of exogenous OXT restored the social preference of adolescent VPA rats. Additionally, early postnatal OXT treatment had long-term effects ameliorating the social impairments and repetitive behaviors of VPA rats until adolescence. This was accompanied by an increase in OXT-ir cells. Taken together, we demonstrated there was central OXT deficiency in the VPA-induced rat model of autism, and showed evidence that early postnatal OXT treatment had a long-term therapeutic effect on the autistic-like behaviors in VPA rats.
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Affiliation(s)
- Yu-Chuan Dai
- Neuroscience Research Institute, Peking University, Beijing, China.,Key Laboratory for Neuroscience, Ministry of Education, National Health and Family Planning Commission, Peking University, Beijing, China.,Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Hong-Feng Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, China
| | - Michael Schön
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.,International Graduate School in Molecular Medicine Ulm, Ulm University, Ulm, Germany.,Department of Neurology, Ulm University, Ulm, Germany
| | - Tobias M Böckers
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.,Department of Neurology, Ulm University, Ulm, Germany
| | - Song-Ping Han
- Neuroscience Research Institute, Peking University, Beijing, China.,Key Laboratory for Neuroscience, Ministry of Education, National Health and Family Planning Commission, Peking University, Beijing, China.,Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,Wuxi HANS Health Medical Technology Co., Ltd., Wuxi, China
| | - Ji-Sheng Han
- Neuroscience Research Institute, Peking University, Beijing, China.,Key Laboratory for Neuroscience, Ministry of Education, National Health and Family Planning Commission, Peking University, Beijing, China.,Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Rong Zhang
- Neuroscience Research Institute, Peking University, Beijing, China.,Key Laboratory for Neuroscience, Ministry of Education, National Health and Family Planning Commission, Peking University, Beijing, China.,Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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45
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Hou Q, Wang Y, Li Y, Chen D, Yang F, Wang S. A Developmental Study of Abnormal Behaviors and Altered GABAergic Signaling in the VPA-Treated Rat Model of Autism. Front Behav Neurosci 2018; 12:182. [PMID: 30186123 PMCID: PMC6110947 DOI: 10.3389/fnbeh.2018.00182] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 08/02/2018] [Indexed: 11/13/2022] Open
Abstract
Although studies have investigated the role of gamma-aminobutyric acid (GABA)ergic signaling in rodent neural development and behaviors relevant to autism, behavioral ontogeny, as underlain by the changes in GABAergic system, is poorly characterized in different brain regions. Here, we employed a valproic acid (VPA) rat model of autism to investigate the autism-like behaviors and GABAergic glutamic acid decarboxylase 67 (GAD67) expression underlying these altered behaviors in multiple brain areas at different developmental stages from birth to adulthood. We found that VPA-treated rats exhibited behavioral abnormalities relevant to autism, including delayed nervous reflex development, altered motor coordination, delayed sensory development, autistic-like and anxiety behaviors and impaired spatial learning and memory. We also found that VPA rats had the decreased expression of GAD67 in the hippocampus (HC) and cerebellum from childhood to adulthood, while decreased GAD67 expression of the temporal cortex (TC) was only observed in adulthood. Conversely, GAD67 expression was increased in the prefrontal cortex (PFC) from adolescence to adulthood. The dysregulated GAD67 expression could alter the excitatory-inhibitory balance in the cerebral cortex, HC and cerebellum. Our findings indicate an impaired GABAergic system could be a major etiological factor occurring in the cerebral cortex, HC and cerebellum of human cases of autism, which suggests enhancement of GABA signaling would be a promising therapeutic target for its treatment.
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Affiliation(s)
- Qianling Hou
- Cerebrovascular Disease Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.,Department of Physiology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Yan Wang
- Cerebrovascular Disease Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.,Department of Physiology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Yingbo Li
- Cerebrovascular Disease Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.,Department of Physiology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Di Chen
- Cerebrovascular Disease Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.,Department of Physiology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Feng Yang
- Lieber Institute for Brain Development, Johns Hopkins University Medical Center, Baltimore, MD, United States
| | - Shali Wang
- Cerebrovascular Disease Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.,Department of Physiology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
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46
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Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism. Transl Psychiatry 2018; 8:148. [PMID: 30097568 PMCID: PMC6086890 DOI: 10.1038/s41398-018-0214-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 06/07/2018] [Accepted: 06/20/2018] [Indexed: 02/07/2023] Open
Abstract
The identification of brain-targeted autoantibodies in children with autism spectrum disorder (ASD) raises the possibility of autoimmune encephalopathy (AIE). Intravenous immunoglobulin (IVIG) is effective for AIE and for some children with ASD. Here, we present the largest case series of children with ASD treated with IVIG. Through an ASD clinic, we screened 82 children for AIE, 80 of them with ASD. IVIG was recommended for 49 (60%) with 31 (38%) receiving the treatment under our care team. The majority of parents (90%) reported some improvement with 71% reporting improvements in two or more symptoms. In a subset of patients, Aberrant Behavior Checklist (ABC) and/or Social Responsiveness Scale (SRS) were completed before and during IVIG treatment. Statistically significant improvement occurred in the SRS and ABC. The antidopamine D2L receptor antibody, the anti-tubulin antibody and the ratio of the antidopamine D2L to D1 receptor antibodies were related to changes in the ABC. The Cunningham Panel predicted SRS, ABC, parent-based treatment responses with good accuracy. Adverse effects were common (62%) but mostly limited to the infusion period. Only two (6%) patients discontinued IVIG because of adverse effects. Overall, our open-label case series provides support for the possibility that some children with ASD may benefit from IVIG. Given that adverse effects are not uncommon, IVIG treatment needs to be considered cautiously. We identified immune biomarkers in select IVIG responders but larger cohorts are needed to study immune biomarkers in more detail. Our small open-label exploratory trial provides evidence supporting a neuroimmune subgroup in patients with ASD.
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47
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Chaihulonggumulitang Shows Psycho-cardiology Therapeutic Effects on Acute Myocardial Infarction by Enhancing Bone Marrow Mesenchymal Stem Cells Mobilization. Sci Rep 2018; 8:3724. [PMID: 29487305 PMCID: PMC5829256 DOI: 10.1038/s41598-018-21789-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 02/09/2018] [Indexed: 12/25/2022] Open
Abstract
Ischemic myocardium initiates the mobilization and homing of bone marrow mesenchymal stem cells (BM-MSCs) to promote myocardial regeneration after acute myocardial infarction (AMI). Inflammation caused by necrotic cardiomyocytes induce major pathological changes (cardiac remodeling and myocardial apoptosis) as well as anxiety disorder. This process may be inhibited by the differentiation and paracrine effects of BM-MSCs. However, the spontaneous mobilization of BMSCs is insufficient to prevent this effect. Given the anti-inflammatory effects of BM-MSCs, ventricular remodeling and anxiety following AMI, methods focused on enhancing BMSCs mobilization are promising. BFG is a classical traditional Chinese prescription medicine and has been proved effective in treating AMI and reducing anxiety, but the potential mechanism of its function remains unknown. In the present study, we explored the effects of Chaihulonggumulitang (BFG) on AMI and anxiety in vivo and in vitro. We also tested its effects in promoting BMSCs mobilization and alleviating inflammation. Our data showed that the classical Chinese prescription BFG promoted BM-MSCs mobilization, inhibited inflammatory response, and improved heart damage and anxiety developed from AMI. Thus, we provided an underlying mechanism of BFG function in psycho-cardiology conditions such as AMI.
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48
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Choi J, Lee S, Won J, Jin Y, Hong Y, Hur TY, Kim JH, Lee SR, Hong Y. Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model. PLoS One 2018; 13:e0192925. [PMID: 29447237 PMCID: PMC5814017 DOI: 10.1371/journal.pone.0192925] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 02/01/2018] [Indexed: 12/22/2022] Open
Abstract
Autism spectrum disorder (ASD) is induced by complex hereditary and environmental factors. However, the mechanisms of ASD development are poorly understood. The purpose of this study was to identify standard indicators of this condition by comparing clinical, pathophysiological, and neurobehavioral features in an autism-like animal model. A total of 22 male Sprague-Dawley rats were randomly divided into control and 500 mg/kg propionic acid (PPA)-treated groups. Rats were subjected to behavioral tests, gene expression analyses, and histological analyses to detect pathophysiological and neurobehavioral alterations. Exploratory activity and non-aggressive behavior were significantly reduced in PPA-treated rats, whereas enhanced aggressive behavior during adjacent interactions was observed on day 14 after PPA administration. To evaluate gene expression after PPA administration, we analyzed hippocampal tissue using reverse transcription PCR. Glial fibrillary acidic protein was augmented in the PPA-treated group on day 14 after appearance of ASD-like behaviors by PPA administration, whereas octamer-binding transcription factor 4 expression was significantly decreased in the PPA-treated group. Histological evaluation revealed significantly reduced diameter and layer thickness of granule cells in PPA-treated rats compared with control rats. We conclude that PPA administration induced abnormal neural cell organization, which may have led to autism-like neurobehaviors, including increased aggressive behavior, reduced exploratory activity, and isolative and passive behaviors.
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Affiliation(s)
- Jeonghyun Choi
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
- Biohealth Products Research Center (BPRC), Inje University, Gimhae, Korea
- Ubiquitous Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gimhae, Korea
| | - Seunghoon Lee
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
- Biohealth Products Research Center (BPRC), Inje University, Gimhae, Korea
- Ubiquitous Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gimhae, Korea
| | - Jinyoung Won
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
- Biohealth Products Research Center (BPRC), Inje University, Gimhae, Korea
- Ubiquitous Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gimhae, Korea
| | - Yunho Jin
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
- Biohealth Products Research Center (BPRC), Inje University, Gimhae, Korea
- Ubiquitous Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gimhae, Korea
| | - Yunkyung Hong
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
- Biohealth Products Research Center (BPRC), Inje University, Gimhae, Korea
- Ubiquitous Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gimhae, Korea
- Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University, Gimhae, Korea
| | - Tai-Young Hur
- Animal Biotechnology Division, National Institute of Animal Science, Wanju, Korea
| | - Joo-Heon Kim
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea
| | - Sang-Rae Lee
- National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
- * E-mail: (YH); (SRL)
| | - Yonggeun Hong
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
- Biohealth Products Research Center (BPRC), Inje University, Gimhae, Korea
- Ubiquitous Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gimhae, Korea
- Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University, Gimhae, Korea
- * E-mail: (YH); (SRL)
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49
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Dong N, Du P, Hao X, He Z, Hou W, Wang L, Yuan W, Yang J, Jia R, Tai F. Involvement of GABA A receptors in the regulation of social preference and emotional behaviors by oxytocin in the central amygdala of female mandarin voles. Neuropeptides 2017; 66:8-17. [PMID: 28764883 DOI: 10.1016/j.npep.2017.07.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 05/19/2017] [Accepted: 07/24/2017] [Indexed: 12/31/2022]
Abstract
The central nucleus of the amygdala (CeA) is the main output of the amygdala and plays an important role in behavioral and neuroendocrine responses to stress. Receptors for the neuropeptide oxytocin (OT) and GABAA are found in high concentration in the CeA. The mechanisms underlying regulation of CeA OT in emotional and social behavior remain unclear. In this study we evaluated the effects of intra-CeA OT administration of different doses (0.1, 1 and 10ng/side), OT receptor antagonist (OTR-A) (1, 10 and 100ng/side) and OT plus OTR-A on social and emotional behavior using a social preference paradigm, open field test and elevated plus maze test in female monogamous mandarin voles (Microtus mandarinus). We then examined whether different doses of the GABAA receptor antagonist bicuculline (5, 10 and 100ng/side) affected the behavioral changes induced by intra-CeA microinjection of OT (1ng/side). We found that administration of OT to the CeA increased social preference, central area investigation times in the open field test, and visits, transitions and time spent in the open arms in the elevated plus maze test; all responses were dose-dependent. Administration of OT plus OTR-A to the CeA produced no effects. Administration of bicuculline in combination with OT to the CeA decreased social preference, central area investigation times in the open field test, and visits, transitions and time spent in the open arms of the elevated plus maze test. These data suggest that OT in the CeA facilitates sociality and reduces levels of anxiety by interacting with local GABAA receptors.
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Affiliation(s)
- Na Dong
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710100, China
| | - Peirong Du
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710100, China
| | - Xin Hao
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710100, China
| | - Zhixiong He
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710100, China
| | - Wenjuan Hou
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710100, China
| | - Limin Wang
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710100, China
| | - Wei Yuan
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710100, China
| | - Jinfeng Yang
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710100, China
| | - Rui Jia
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710100, China.
| | - Fadao Tai
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710100, China.
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50
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Zhang JP, Zhang KY, Guo L, Chen QL, Gao P, Wang T, Li J, Guo GZ, Ding GR. Effects of 1.8 GHz Radiofrequency Fields on the Emotional Behavior and Spatial Memory of Adolescent Mice. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2017; 14:E1344. [PMID: 29113072 PMCID: PMC5707983 DOI: 10.3390/ijerph14111344] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 10/31/2017] [Accepted: 11/02/2017] [Indexed: 11/16/2022]
Abstract
The increasing use of mobile phones by teenagers has raised concern about the cognitive effects of radiofrequency (RF) fields. In this study, we investigated the effects of 4-week exposure to a 1.8 GHz RF field on the emotional behavior and spatial memory of adolescent male mice. Anxiety-like behavior was evaluated by open field test (OFT) and elevated plus maze (EPM) test, while depression-like behavior was evaluated by sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST). The spatial learning and memory ability were evaluated by Morris water maze (MWM) experiments. The levels of amino acid neurotransmitters were determined by liquid chromatography-mass spectrometry (LC-MS). The histology of the brain was examined by hematoxylin-eosin (HE) staining. It was found that the depression-like behavior, spatial memory ability and histology of the brain did not change obviously after RF exposure. However, the anxiety-like behavior increased in mice, while, the levels of γ-aminobutyric acid (GABA) and aspartic acid (Asp) in cortex and hippocampus significantly decreased after RF exposure. These data suggested that RF exposure under these conditions do not affect the depression-like behavior, spatial memory and brain histology in adolescent male mice, but it may however increase the level of anxiety, and GABA and Asp were probably involved in this effect.
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Affiliation(s)
- Jun-Ping Zhang
- Department of Radiation Biology, Faculty of Preventive Medicine, Fourth Military Medical University, 169# Chang Le West Road, Xi'an 710032, China.
| | - Ke-Ying Zhang
- Department of Radiation Biology, Faculty of Preventive Medicine, Fourth Military Medical University, 169# Chang Le West Road, Xi'an 710032, China.
| | - Ling Guo
- Department of Radiation Biology, Faculty of Preventive Medicine, Fourth Military Medical University, 169# Chang Le West Road, Xi'an 710032, China.
| | - Qi-Liang Chen
- Department of Radiation Biology, Faculty of Preventive Medicine, Fourth Military Medical University, 169# Chang Le West Road, Xi'an 710032, China.
| | - Peng Gao
- Department of Radiation Medicine, Faculty of Preventive Medicine, Fourth Military Medical University, 169# Chang Le West Road, Xi'an 710032, China.
| | - Tian Wang
- Department of Radiation Biology, Faculty of Preventive Medicine, Fourth Military Medical University, 169# Chang Le West Road, Xi'an 710032, China.
| | - Jing Li
- Department of Radiation Biology, Faculty of Preventive Medicine, Fourth Military Medical University, 169# Chang Le West Road, Xi'an 710032, China.
| | - Guo-Zhen Guo
- Department of Radiation Medicine, Faculty of Preventive Medicine, Fourth Military Medical University, 169# Chang Le West Road, Xi'an 710032, China.
| | - Gui-Rong Ding
- Department of Radiation Biology, Faculty of Preventive Medicine, Fourth Military Medical University, 169# Chang Le West Road, Xi'an 710032, China.
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