|
1
|
Gonzalez L, Bezzi P. Astrocyte Dysfunctions in Obsessive Compulsive Disorder: Rethinking Neurobiology and Therapeutic Targets. J Neurochem 2025; 169:e70092. [PMID: 40400176 PMCID: PMC12095986 DOI: 10.1111/jnc.70092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/30/2025] [Accepted: 05/12/2025] [Indexed: 05/23/2025]
Abstract
Obsessive-compulsive disorder (OCD) has long been conceptualized as a neuron-centric disorder of cortico-striato-thalamo-cortical (CSTC) circuit dysregulation. However, a growing body of evidence is now reframing this narrative, placing astrocytes-once relegated to passive support roles-at the center of OCD pathophysiology. Astrocytes are critical regulators of glutamate and GABA homeostasis, calcium signaling, and synaptic plasticity, all of which are disrupted in OCD. Recent high-resolution molecular and proteomic studies reveal that specific astrocyte subpopulations, including Crym-positive astrocytes, directly shape excitatory/inhibitory balance and control perseverative behaviors by modulating presynaptic inputs from the orbitofrontal cortex. Disruptions in astrocytic neurotransmitter clearance and dopamine metabolism amplify CSTC circuit hyperactivity and reinforce compulsions. This review reframes OCD as a disorder of neuro-glial dysfunctions, proposing that targeting astrocytic signaling, metabolism, and structural plasticity may unlock transformative therapeutic strategies. By integrating human and animal data, we advocate for a glial-centric model of OCD that not only enhances mechanistic understanding but also opens new frontiers for precision treatment.
Collapse
Affiliation(s)
- Laurine Gonzalez
- Department of Fundamental Neurosciences (DNF)University of Lausanne (UNIL)LausanneSwitzerland
| | - Paola Bezzi
- Department of Fundamental Neurosciences (DNF)University of Lausanne (UNIL)LausanneSwitzerland
- Department of Physiology and PharmacologyUniversity of Rome SapienzaRomeItaly
| |
Collapse
|
|
2
|
Alabdali A, Ben Bacha A, Alonazi M, Al-Ayadhi LY, Alanazi ASJ, El‐Ansary A. Comparative evaluation of certain biomarkers emphasizing abnormal GABA inhibitory effect and glutamate excitotoxicity in autism spectrum disorders. Front Psychiatry 2025; 16:1562631. [PMID: 40330649 PMCID: PMC12052539 DOI: 10.3389/fpsyt.2025.1562631] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/12/2025] [Indexed: 05/08/2025] Open
Abstract
Introduction Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and repetitive behaviors. An imbalance between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) might play a crucial role in ASD. This study explores the biochemical markers associated with GABAergic and glutamatergic signaling in individuals with autism and healthy controls, aiming to identify potential diagnostic and therapeutic targets. Methods The study included 46 male individuals with autism and 26 age- and gender-matched healthy controls. The plasma levels of excitatory amino acid transporter 2 (EAAT2), potassium chloride co-transporter 2 (KCC2), Na-K-Cl co-transporter 1 (NKCC1), vitamin D3 (VD3), GABA, gamma aminobutyric acid type a receptor subunit alpha 5 (GABRA5), and glutamate were measured using ELISA. Statistical analyses, including correlation, multiple regression, and receiver operating characteristic (ROC) curve analysis, were performed to evaluate the diagnostic utility and interrelationships of these biomarkers. Results Significant biochemical differences were found between individuals with autism and healthy controls. Individuals with autism had notably lower levels of EAAT2, KCC2, NKCC1, VD3, GABA, and GABRA5, especially in the severe group. Altered KCC2/NKCC1 and GABA/glutamate ratios highlighted the imbalance in neurotransmission. The correlation and multiple regression analyses showed significant interconnections between biomarkers. The ROC analysis indicated that EAAT2, KCC2, GABA, and the ratios of KCC2/NKCC1 and GABA/glutamate have high diagnostic potential. Conclusion These findings support the hypothesis that GABA and glutamate imbalance is central to the pathophysiology of ASD. Significant disruptions in neurotransmitter signaling and chloride homeostasis, particularly in severe cases, provide insights into the neurobiological mechanisms of ASD. Restoring the GABA-glutamate balance could be an effective therapeutic strategy for ASD, warranting further research into these biochemical pathways for targeted treatments.
Collapse
Affiliation(s)
- Altaf Alabdali
- Biochemistry Department, Science College, King Saud University, Riyadh, Saudi Arabia
| | - Abir Ben Bacha
- Biochemistry Department, Science College, King Saud University, Riyadh, Saudi Arabia
| | - Mona Alonazi
- Biochemistry Department, Science College, King Saud University, Riyadh, Saudi Arabia
| | - Laila Y. Al-Ayadhi
- Autism Research and Treatment Center, Department of Physiology, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
| | | | - Afaf El‐Ansary
- Autism Center, Lotus Holistic Alternative Medical Center, Abu Dhabi, United Arab Emirates
| |
Collapse
|
|
3
|
Gómez-Gonzalo M. Astrocytes in Rodent Anxiety-Related Behavior: Role of Calcium and Beyond. Int J Mol Sci 2025; 26:2774. [PMID: 40141416 PMCID: PMC11943343 DOI: 10.3390/ijms26062774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 03/28/2025] Open
Abstract
Anxiety is a physiological, emotional response that anticipates distal threats. When kept under control, anxiety is a beneficial response, helping animals to maintain heightened attention in environments with potential dangers. However, an overestimation of potential threats can lead to an excessive expression of anxiety that, in humans, may evolve into anxiety disorders. Pharmacological treatments show variable efficacy among patients, highlighting the need for more efforts to better understand the pathogenesis of anxiety disorders. Mounting evidence suggests that astrocytes, a type of glial cells, are active partners of neurons in brain circuits and in the regulation of behaviors under both physiological and pathological conditions. In this review, I summarize the current literature on the role of astrocytes from different brain regions in modulating anxious states, with the goal of exploring novel cerebral mechanisms to identify potential innovative therapeutic targets for the treatment of anxiety disorders.
Collapse
Affiliation(s)
- Marta Gómez-Gonzalo
- Section of Padua, Neuroscience Institute, National Research Council (CNR), 35131 Padua, Italy
| |
Collapse
|
|
4
|
Wu X, Hao J, Jiang K, Wu M, Zhao X, Zhang X. Neuroinflammation and pathways that contribute to tourette syndrome. Ital J Pediatr 2025; 51:63. [PMID: 40022157 PMCID: PMC11871796 DOI: 10.1186/s13052-025-01874-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 01/26/2025] [Indexed: 03/03/2025] Open
Abstract
Tourette syndrome (TS), a neurological and psychological disease, typically exhibit motor and phonic tics. The pathophysiology of TS remains controversial. Currently, the recognized pathogenesis of TS is the imbalance of neurotransmitters, involving abnormality of the cortex-striatum-thalamus-cortex circuit. Recently, clinical researches demonstrate that triggers such as infection and allergic reaction could lead to the onset or exacerbation of tic symptoms. Current studies have also suggested that neural-immune crosstalk caused by inflammation is also associated with TS, potentially leading to the occurrence of tics by inducing neurotransmitter abnormalities. Herein, we review inflammation-related factors contributing to the occurrence of TS as well as the mechanisms by which immune-inflammatory pathways mediate the onset of TS. This aims to clarify the pathogenesis of TS and provide a theoretical basis for the treatment of TS.
Collapse
Affiliation(s)
- Xinnan Wu
- Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Juanjuan Hao
- School of Medicine, Shaoxing University, Shaoxing, China
| | - Keyu Jiang
- Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Wu
- Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xin Zhao
- Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xin Zhang
- Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
5
|
Frick LR. Neuroglia in Tourette syndrome and obsessive-compulsive disorder. HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:325-334. [PMID: 40148053 DOI: 10.1016/b978-0-443-19102-2.00005-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
In recent years, neuroglia have drawn the attention of researchers in the fields of neurology and psychiatry. Besides their well-known functions providing support to neurons, myelinating axons, and clearing up debris, a constantly growing of evidence indicates that glial cells are key contributors to the pathophysiology of neuropsychiatric disorders. Alterations in microglia, astrocytes, and oligodendrocytes have been described in Tourette syndrome (TS) and obsessive-compulsive disorder (OCD). The sudden onset of tics and OCD-like symptoms after infection in children (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections) suggests a connection with the immune system; in fact, neuroinflammation has been reported. Many imaging studies revealed abnormal myelination in the brain of TS and OCD patients, highlighting the implication of oligodendroglia in the connectivity alterations. Moreover, animal models have unveiled a cell-autonomous role of microglia and astrocytes in the etiology of pathologic grooming, which links these glial cells to the related disorder trichotillomania. This chapter reviews the state of the art and current gaps in the literature, proposing possible pathomechanisms and future research directions.
Collapse
Affiliation(s)
- Luciana R Frick
- Departments of Neurology and Medicine, Neuroscience Graduate Program, Jacobs School of Medicine & Biomedical Sciences, State University of New York at Buffalo, Clinical and Translational Research Center, Buffalo, NY, United States.
| |
Collapse
|
|
6
|
Heine VM, Dooves S. Neuroglia in autism spectrum disorders. HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:303-311. [PMID: 40148051 DOI: 10.1016/b978-0-443-19102-2.00006-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Autism spectrum disorder (ASD) is characterized by difficulties in social interaction, communication, and repetitive behavior, typically diagnosed during early childhood and attributed to altered neuronal network connectivity. Several genetic and environmental risk factors contribute to ASD, including pre- or early life immune activation, which can trigger microglial and astroglial reactivity, impacting early neurodevelopment. In ASD, astrocytes show altered glutamate metabolism, directly influencing neuronal network activity, while microglia display impaired synaptic pruning, an essential developmental process for the refinement of neuronal connections. Additionally, reduced myelination in specific cortical and subcortical regions may affect brain connectivity in ASD, with white matter integrity correlating with the severity of the disorder, suggesting an important role for oligodendrocytes and myelin in ASD. This chapter provides an overview of current literature on the role of neuroglia cells in ASD, with a focus on immune activation, glutamate signaling, synaptic pruning, and myelination.
Collapse
Affiliation(s)
- Vivi M Heine
- Department of Child and Adolescence Psychiatry, Emma Center for Personalized Medicine, Amsterdam Neuroscience, Emma Children's Hospital, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.
| | - Stephanie Dooves
- Department of Child and Adolescence Psychiatry, Emma Center for Personalized Medicine, Amsterdam Neuroscience, Emma Children's Hospital, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
| |
Collapse
|
|
7
|
Singhvi A, Shaham S, Rapti G. Glia Development and Function in the Nematode Caenorhabditis elegans. Cold Spring Harb Perspect Biol 2024; 16:a041346. [PMID: 38565269 PMCID: PMC11445397 DOI: 10.1101/cshperspect.a041346] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
The nematode Caenorhabditis elegans is a powerful experimental setting for uncovering fundamental tenets of nervous system organization and function. Its nearly invariant and simple anatomy, coupled with a plethora of methodologies for interrogating single-gene functions at single-cell resolution in vivo, have led to exciting discoveries in glial cell biology and mechanisms of glia-neuron interactions. Findings over the last two decades reinforce the idea that insights from C. elegans can inform our understanding of glial operating principles in other species. Here, we summarize the current state-of-the-art, and describe mechanistic insights that have emerged from a concerted effort to understand C. elegans glia. The remarkable acceleration in the pace of discovery in recent years paints a portrait of striking molecular complexity, exquisite specificity, and functional heterogeneity among glia. Glial cells affect nearly every aspect of nervous system development and function, from generating neurons, to promoting neurite formation, to animal behavior, and to whole-animal traits, including longevity. We discuss emerging questions where C. elegans is poised to fill critical knowledge gaps in our understanding of glia biology.
Collapse
Affiliation(s)
- Aakanksha Singhvi
- Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA
- Department of Biological Structure, University of Washington School of Medicine, Seattle, Washington 98195, USA
| | - Shai Shaham
- Laboratory of Developmental Genetics, The Rockefeller University, New York, New York 10065, USA
| | - Georgia Rapti
- Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
- Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory, Monterotondo, Rome 00015, Italy
- Interdisciplinary Center of Neurosciences, Heidelberg University, Heidelberg, Germany
| |
Collapse
|
|
8
|
Lu MQ, Shi ZG, Shang J, Gao L, Gao L, Gao WJ. ChangPu YuJin Tang improves Tourette disorder symptoms by modulating amino acid neurotransmitters in IDPN model rats. Metab Brain Dis 2024; 39:1543-1558. [PMID: 39312065 DOI: 10.1007/s11011-024-01411-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 08/09/2024] [Indexed: 11/05/2024]
Abstract
INTRODUCTION Changpu Yujin Tang(CPYJT), a Chinese herbal compound, is an effective therapeutic strategy for pediatric patients with Tourette disorder (TD). Therefore, this work aims to investigate the therapeutic mechanisms of CPYJT. METHODS Behavioral and cellular ultrastructural evaluation of the therapeutic effects of CPYJT in TD model rats. Colorimetric methods, reverse transcription‑quantitative PCR, and Western Blot were used to measure the altered levels of GLU, GABA, and the levels of VGLUT1, GLUD1, GABRA3, and GAD65 in the cortex, striatum, and thalamus of the TD model rats after 7, 14, 21, and 28 days of CPYJT administration. RESULTS CPYJT significantly reduced stereotypic behavior and motor behavior scores in TD model rats. CPYJT ameliorates myelin structural damage in TD model rat neuronal cells. CPYJT decreased GLU content, elevated GABA content, decreased GLUD1 and VGLUT1 levels, and elevated GAD65 and GABRA3 levels in TD model rats' cortex, striatum, and thalamus. CPYJT has different regulatory time points in the cortex, striatum, and thalamus for critical factors of amino acid-based neurotransmission. CONCLUSION CPYJT protects behavioral and structural damage of neuronal cells in multiple brain regions in TD model rats.
Collapse
Affiliation(s)
- Man-Qi Lu
- Clinical College of Chinese Medicine, Gansu University Of Chinese Medicine, Lanzhou, 730000, Gansu, P.R. China
- Longhua Hospital Shanghai University of Traditional Chinese Medicine, shanghai, 200000, China
| | - Zheng-Gang Shi
- Clinical College of Chinese Medicine, Gansu University Of Chinese Medicine, Lanzhou, 730000, Gansu, P.R. China.
| | - Jing Shang
- Clinical College of Chinese Medicine, Gansu University Of Chinese Medicine, Lanzhou, 730000, Gansu, P.R. China
| | - Lü Gao
- Shanxi University Of Chinese Medicine Third Clinical Medical College Pediatric Teaching and Research Department, Taiyuan, 140100, Shanxi, China
| | - Lei Gao
- Clinical College of Chinese Medicine, Gansu University Of Chinese Medicine, Lanzhou, 730000, Gansu, P.R. China
| | - Wei-Jiao Gao
- Clinical College of Chinese Medicine, Gansu University Of Chinese Medicine, Lanzhou, 730000, Gansu, P.R. China
| |
Collapse
|
|
9
|
Huang H, Lu W, Luo R, Zeng Y, Zhang Y, Su X, Zhang X, Tian B, Wang X. Astrocytic RARγ mediates hippocampal astrocytosis and neurogenesis deficits in chronic retinoic acid-induced depression. Neuropsychopharmacology 2024; 50:419-431. [PMID: 39242924 PMCID: PMC11632084 DOI: 10.1038/s41386-024-01983-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 08/10/2024] [Accepted: 08/28/2024] [Indexed: 09/09/2024]
Abstract
Accumulating clinical evidence indicates that chronic exposure to retinoic acid (RA) may lead to depressive symptoms and even increase the risk of suicidal behavior, which severely limits the clinical long-term application of RA. The exact mechanisms through which RA contributes to the onset of depression remain largely unclear. Here, we administered intraperitoneal injections of all-trans RA to male C57BL/6 J mice over a period of 21 days. Mice subjected to chronic RA exposure displayed depressive-like behaviors, accompanied by impaired hippocampal neurogenesis and heightened RA receptor gamma (RARγ) levels in the ventral hippocampus (vHip). The administration of an RARγ antagonist effectively mitigated these RA-induced neurogenesis impairments and depressive-like behaviors. Chronic exposure to RA was also observed to promote hippocampal astrocytosis and increase astrocytic Rarγ expression in the ventral dentate gyrus (vDG) of hippocampus. Notably, astrocytic RARγ in the vDG was found to be a key factor in the observed hippocampal astrocytosis and neurogenesis impairments, and depressive-like behaviors. Chronic exposure to RA resulted in increased extracellular glutamate levels in neural stem cells (NSCs), accompanied by a decrease in glutamate transporter 1 (GLT-1) expression. Enhancing astrocytic GLT-1 expression was found to alleviate both hippocampal astrocytosis and depressive-like behaviors caused by RA. These findings underscore the critical role of astrocytic RARγ-GLT-1 axis in the development of hippocampal astrocytosis, neurogenesis impairments, and depressive symptoms, suggesting that targeting RARγ-GLT-1 could potentially offer an effective therapeutic approach for depression.
Collapse
Affiliation(s)
- Huixian Huang
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Wensi Lu
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Ran Luo
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yinyun Zeng
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuqin Zhang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaohong Su
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Xinyi Zhang
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Bo Tian
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Xuemin Wang
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
| |
Collapse
|
|
10
|
Soto JS, Neupane C, Kaur M, Pandey V, Wohlschlegel JA, Khakh BS. Astrocyte Gi-GPCR signaling corrects compulsive-like grooming and anxiety-related behaviors in Sapap3 knockout mice. Neuron 2024; 112:3412-3423.e6. [PMID: 39163865 PMCID: PMC11512628 DOI: 10.1016/j.neuron.2024.07.019] [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: 01/28/2024] [Revised: 05/06/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024]
Abstract
Astrocytes are morphologically complex cells that serve essential roles. They are widely implicated in central nervous system (CNS) disorders, with changes in astrocyte morphology and gene expression accompanying disease. In the Sapap3 knockout (KO) mouse model of compulsive and anxiety-related behaviors related to obsessive-compulsive disorder (OCD), striatal astrocytes display reduced morphology and altered actin cytoskeleton and Gi-G-protein-coupled receptor (Gi-GPCR) signaling proteins. Here, we show that normalizing striatal astrocyte morphology, actin cytoskeleton, and essential homeostatic support functions by targeting the astrocyte Gi-GPCR pathway using chemogenetics corrected phenotypes in Sapap3 KO mice, including anxiety-related and compulsive behaviors. Our data portend an astrocytic pharmacological strategy for rescuing phenotypes in brain disorders that include compromised astrocyte morphology and tissue support.
Collapse
Affiliation(s)
- Joselyn S Soto
- Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
| | - Chiranjivi Neupane
- Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA
| | - Muskan Kaur
- Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA
| | - Vijaya Pandey
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA
| | - James A Wohlschlegel
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA
| | - Baljit S Khakh
- Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
| |
Collapse
|
|
11
|
Li J, Jin S, Hu J, Xu R, Xu J, Li Z, Wang M, Fu Y, Liao S, Li X, Chen Y, Gao T, Yang J. Astrocytes in the Ventral Hippocampus Bidirectionally Regulate Innate and Stress-Induced Anxiety-Like Behaviors in Male Mice. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400354. [PMID: 39120568 PMCID: PMC11481230 DOI: 10.1002/advs.202400354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/29/2024] [Indexed: 08/10/2024]
Abstract
The mechanisms of anxiety disorders, the most common mental illness, remain incompletely characterized. The ventral hippocampus (vHPC) is critical for the expression of anxiety. However, current studies primarily focus on vHPC neurons, leaving the role for vHPC astrocytes in anxiety largely unexplored. Here, genetically encoded Ca2+ indicator GCaMP6m and in vivo fiber photometry calcium imaging are used to label vHPC astrocytes and monitor their activity, respectively, genetic and chemogenetic approaches to inhibit and activate vHPC astrocytes, respectively, patch-clamp recordings to measure glutamate currents, and behavioral assays to assess anxiety-like behaviors. It is found that vHPC astrocytic activity is increased in anxiogenic environments and by 3-d subacute restraint stress (SRS), a well-validated mouse model of anxiety disorders. Genetic inhibition of vHPC astrocytes exerts anxiolytic effects on both innate and SRS-induced anxiety-related behaviors, whereas hM3Dq-mediated chemogenetic or SRS-induced activation of vHPC astrocytes enhances anxiety-like behaviors, which are reversed by intra-vHPC application of the ionotropic glutamate N-methyl-d-aspartate receptor antagonists. Furthermore, intra-vHPC or systemic application of the N-methyl-d-aspartate receptor antagonist memantine, a U.S. FDA-approved drug for Alzheimer's disease, fully rescues SRS-induced anxiety-like behaviors. The findings highlight vHPC astrocytes as critical regulators of stress and anxiety and as potential therapeutic targets for anxiety and anxiety-related disorders.
Collapse
Affiliation(s)
- Jing‐Ting Li
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Shi‐Yang Jin
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Jian Hu
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Ru‐Xia Xu
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Jun‐Nan Xu
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Zi‐Ming Li
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Meng‐Ling Wang
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Yi‐Wen Fu
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Shi‐Han Liao
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Xiao‐Wen Li
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Yi‐Hua Chen
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Tian‐Ming Gao
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| | - Jian‐Ming Yang
- State Key Laboratory of Organ Failure ResearchKey Laboratory of Mental Health of the Ministry of EducationGuangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceGuangdong Province Key Laboratory of Psychiatric DisordersDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong510515China
| |
Collapse
|
|
12
|
Grassi G, Scillitani E, Cecchelli C. New horizons for obsessive-compulsive disorder drug discovery: is targeting glutamate receptors the answer? Expert Opin Drug Discov 2024; 19:1235-1245. [PMID: 39105546 DOI: 10.1080/17460441.2024.2387127] [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: 04/06/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024]
Abstract
INTRODUCTION Over the past decade, glutamate has emerged as a prominent focus in the field of obsessive-compulsive disorder (OCD) pathophysiology. A convergence of evidence from genetic, preclinical, and clinical studies points to glutamatergic dysfunction as a key feature of this condition. In light of these findings, there has been a growing interest in exploring the potential of glutamatergic agents in the treatment of OCD. AREAS COVERED This paper reviews the literature on glutamate transmission in OCD. In addition, the authors examine the results of clinical trials investigating the efficacy of glutamatergic agents in the treatment of OCD patients. EXPERT OPINION Along with the recognition of neuroinflammation in the brain in OCD, the evidence of glutamate dysfunction represents one of the most promising recent discoveries for understanding the mechanisms involved in OCD. The importance of this discovery lies primarily in its pharmacological implications and has led to intense research activity in the field of glutamatergic agents. While this research has not yet had a substantial clinical impact, targeting glutamate receptors remains a promising horizon for the successful treatment of OCD patients.
Collapse
Affiliation(s)
- Giacomo Grassi
- Department of Psychiatry, Brain Center Firenze, Florence, Italy
| | | | | |
Collapse
|
|
13
|
Vivi E, Di Benedetto B. Brain stars take the lead during critical periods of early postnatal brain development: relevance of astrocytes in health and mental disorders. Mol Psychiatry 2024; 29:2821-2833. [PMID: 38553540 PMCID: PMC11420093 DOI: 10.1038/s41380-024-02534-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 03/12/2024] [Accepted: 03/14/2024] [Indexed: 09/25/2024]
Abstract
In the brain, astrocytes regulate shape and functions of the synaptic and vascular compartments through a variety of released factors and membrane-bound proteins. An imbalanced astrocyte activity can therefore have drastic negative impacts on brain development, leading to the onset of severe pathologies. Clinical and pre-clinical studies show alterations in astrocyte cell number, morphology, molecular makeup and astrocyte-dependent processes in different affected brain regions in neurodevelopmental (ND) and neuropsychiatric (NP) disorders. Astrocytes proliferate, differentiate and mature during the critical period of early postnatal brain development, a time window of elevated glia-dependent regulation of a proper balance between synapse formation/elimination, which is pivotal in refining synaptic connectivity. Therefore, any intrinsic and/or extrinsic factors altering these processes during the critical period may result in an aberrant synaptic remodeling and onset of mental disorders. The peculiar bridging position of astrocytes between synaptic and vascular compartments further allows them to "compute" the brain state and consequently secrete factors in the bloodstream, which may serve as diagnostic biomarkers of distinct healthy or disease conditions. Here, we collect recent advancements regarding astrogenesis and astrocyte-mediated regulation of neuronal network remodeling during early postnatal critical periods of brain development, focusing on synapse elimination. We then propose alternative hypotheses for an involvement of aberrancies in these processes in the onset of ND and NP disorders. In light of the well-known differential prevalence of certain brain disorders between males and females, we also discuss putative sex-dependent influences on these neurodevelopmental events. From a translational perspective, understanding age- and sex-dependent astrocyte-specific molecular and functional changes may help to identify biomarkers of distinct cellular (dys)functions in health and disease, favouring the development of diagnostic tools or the selection of tailored treatment options for male/female patients.
Collapse
Affiliation(s)
- Eugenia Vivi
- Laboratory of Neuro-Glia Pharmacology, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053, Regensburg, Germany
| | - Barbara Di Benedetto
- Laboratory of Neuro-Glia Pharmacology, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053, Regensburg, Germany.
- Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany.
| |
Collapse
|
|
14
|
Mostafavi Abdolmaleky H, Alam R, Nohesara S, Deth RC, Zhou JR. iPSC-Derived Astrocytes and Neurons Replicate Brain Gene Expression, Epigenetic, Cell Morphology and Connectivity Alterations Found in Autism. Cells 2024; 13:1095. [PMID: 38994948 PMCID: PMC11240613 DOI: 10.3390/cells13131095] [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: 04/12/2024] [Revised: 06/04/2024] [Accepted: 06/19/2024] [Indexed: 07/13/2024] Open
Abstract
Excessive inflammatory reactions and oxidative stress are well-recognized molecular findings in autism and these processes can affect or be affected by the epigenetic landscape. Nonetheless, adequate therapeutics are unavailable, as patient-specific brain molecular markers for individualized therapies remain challenging. METHODS We used iPSC-derived neurons and astrocytes of patients with autism vs. controls (5/group) to examine whether they replicate the postmortem brain expression/epigenetic alterations of autism. Additionally, DNA methylation of 10 postmortem brain samples (5/group) was analyzed for genes affected in PSC-derived cells. RESULTS We found hyperexpression of TGFB1, TGFB2, IL6 and IFI16 and decreased expression of HAP1, SIRT1, NURR1, RELN, GPX1, EN2, SLC1A2 and SLC1A3 in the astrocytes of patients with autism, along with DNA hypomethylation of TGFB2, IL6, TNFA and EN2 gene promoters and a decrease in HAP1 promoter 5-hydroxymethylation in the astrocytes of patients with autism. In neurons, HAP1 and IL6 expression trended alike. While HAP1 promoter was hypermethylated in neurons, IFI16 and SLC1A3 promoters were hypomethylated and TGFB2 exhibited increased promoter 5-hydroxymethlation. We also found a reduction in neuronal arborization, spine size, growth rate, and migration, but increased astrocyte size and a reduced growth rate in autism. In postmortem brain samples, we found DNA hypomethylation of TGFB2 and IFI16 promoter regions, but DNA hypermethylation of HAP1 and SLC1A2 promoters in autism. CONCLUSION Autism-associated expression/epigenetic alterations in iPSC-derived cells replicated those reported in the literature, making them appropriate surrogates to study disease pathogenesis or patient-specific therapeutics.
Collapse
Affiliation(s)
- Hamid Mostafavi Abdolmaleky
- Nutrition/Metabolism Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;
- Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA;
| | - Reza Alam
- Nutrition/Metabolism Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;
| | - Shabnam Nohesara
- Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA;
| | - Richard C. Deth
- Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Jin-Rong Zhou
- Nutrition/Metabolism Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;
| |
Collapse
|
|
15
|
Burton CL, Longaretti A, Zlatanovic A, Gomes GM, Tonini R. Striatal insights: a cellular and molecular perspective on repetitive behaviors in pathology. Front Cell Neurosci 2024; 18:1386715. [PMID: 38601025 PMCID: PMC11004256 DOI: 10.3389/fncel.2024.1386715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 03/15/2024] [Indexed: 04/12/2024] Open
Abstract
Animals often behave repetitively and predictably. These repetitive behaviors can have a component that is learned and ingrained as habits, which can be evolutionarily advantageous as they reduce cognitive load and the expenditure of attentional resources. Repetitive behaviors can also be conscious and deliberate, and may occur in the absence of habit formation, typically when they are a feature of normal development in children, or neuropsychiatric disorders. They can be considered pathological when they interfere with social relationships and daily activities. For instance, people affected by obsessive-compulsive disorder, autism spectrum disorder, Huntington's disease and Gilles de la Tourette syndrome can display a wide range of symptoms like compulsive, stereotyped and ritualistic behaviors. The striatum nucleus of the basal ganglia is proposed to act as a master regulator of these repetitive behaviors through its circuit connections with sensorimotor, associative, and limbic areas of the cortex. However, the precise mechanisms within the striatum, detailing its compartmental organization, cellular specificity, and the intricacies of its downstream connections, remain an area of active research. In this review, we summarize evidence across multiple scales, including circuit-level, cellular, and molecular dimensions, to elucidate the striatal mechanisms underpinning repetitive behaviors and offer perspectives on the implicated disorders. We consider the close relationship between behavioral output and transcriptional changes, and thereby structural and circuit alterations, including those occurring through epigenetic processes.
Collapse
Affiliation(s)
| | | | | | | | - Raffaella Tonini
- Neuromodulation of Cortical and Subcortical Circuits Laboratory, Istituto Italiano di Tecnologia, Genoa, Italy
| |
Collapse
|
|
16
|
Macedo BL, Veloso MF, Dias IB, Ayub JGM, Beijamini V. Sex differences in the anticompulsive-like effect of memantine: Involvement of nitric oxide pathway but not AMPA receptors. Behav Brain Res 2024; 461:114834. [PMID: 38142859 DOI: 10.1016/j.bbr.2023.114834] [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: 10/10/2023] [Revised: 12/21/2023] [Accepted: 12/21/2023] [Indexed: 12/26/2023]
Abstract
Memantine, an N-Methyl-D-Aspartate (NMDA) antagonist, has been examined as a potential treatment for Obsessive-Compulsive Disorder (OCD). Yet, there is limited knowledge regarding how it works to reduce compulsive behaviour and whether it has different effects on individuals based on their sex. Herein, we investigated if there are sex differences in the anticompulsive-like effect of memantine in adult Swiss mice. Additionally, we explored whether the nitric oxide (NO) pathway and α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptors play a role in memantine's effects. To start, we assessed the impact of a single intraperitoneal dose of memantine (at 3, 5, and 10 mg/kg) on behaviours exhibited in the open field test (OFT) and the marble-burying test (MBT), the latter being a predictive test for anticompulsive effects. All doses of memantine reduced marble-burying behaviour in both male and female mice without affecting their locomotor activity in the OFT. This anticompulsive-like effect was also confirmed in another predictive test, the nest-building test, with the highest memantine dose (10 mg/kg) reducing nest-building behaviour without significant differences between male and female mice. We observed that pre-treatment with L-arginine, a NO precursor, mitigated the anticompulsive-like effect of memantine in male mice but had no effect in female mice in the MBT. Finally, NBQX, an AMPA receptor antagonist, did not block the anticompulsive-like effect of memantine. In summary, our study suggests that the anticompulsive-like effect of memantine does not appear to be sex-specific, does not depend on AMPA receptors, and involves the NO pathway primarily in male mice.
Collapse
Affiliation(s)
- Breno Lopes Macedo
- Pharmaceutical Sciences Graduate Program, Health Sciences Centre, Federal University of Espírito Santo, Vitória, ES, Brazil
| | - Mariana Friedrich Veloso
- Department of Pharmaceutical Sciences, Health Science Centre, Federal University of Espírito Santo, Vitória, ES, Brazil
| | - Isabella Braun Dias
- Department of Pharmaceutical Sciences, Health Science Centre, Federal University of Espírito Santo, Vitória, ES, Brazil
| | - Júlia Grigorini Mori Ayub
- Pharmaceutical Sciences Graduate Program, Health Sciences Centre, Federal University of Espírito Santo, Vitória, ES, Brazil
| | - Vanessa Beijamini
- Pharmaceutical Sciences Graduate Program, Health Sciences Centre, Federal University of Espírito Santo, Vitória, ES, Brazil; Department of Pharmaceutical Sciences, Health Science Centre, Federal University of Espírito Santo, Vitória, ES, Brazil.
| |
Collapse
|
|
17
|
Pietrobon D, Conti F. Astrocytic Na +, K + ATPases in physiology and pathophysiology. Cell Calcium 2024; 118:102851. [PMID: 38308916 DOI: 10.1016/j.ceca.2024.102851] [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: 12/13/2023] [Revised: 01/26/2024] [Accepted: 01/26/2024] [Indexed: 02/05/2024]
Abstract
The Na+, K+ ATPases play a fundamental role in the homeostatic functions of astrocytes. After a brief historic prologue and discussion of the subunit composition and localization of the astrocytic Na+, K+ ATPases, the review focuses on the role of the astrocytic Na+, K+ pumps in extracellular K+ and glutamate homeostasis, intracellular Na+ and Ca2+ homeostasis and signaling, regulation of synaptic transmission and neurometabolic coupling between astrocytes and neurons. Loss-of-function mutations in the gene encoding the astrocytic α2 Na+, K+ ATPase cause a rare monogenic form of migraine with aura (familial hemiplegic migraine type 2). On the other hand, the α2 Na+, K+ ATPase is upregulated in spinal cord and brain samples from amyotrophic lateral sclerosis and Alzheimer disease patients, respectively. In the last part, the review focuses on i) the migraine relevant phenotypes shown by familial hemiplegic migraine type 2 knock-in mice with 50 % reduced expression of the astrocytic α2 Na+, K+ ATPase and the insights into the pathophysiology of migraine obtained from these genetic mouse models, and ii) the evidence that upregulation of the astrocytic α2 Na+, K+ ATPase in mouse models of amyotrophic lateral sclerosis and Alzheimer disease promotes neuroinflammation and contributes to progressive neurodegeneration.
Collapse
Affiliation(s)
- Daniela Pietrobon
- Department of Biomedical Sciences and Padova Neuroscience Center (PNC), University of Padova, Padova 35131, Italy.
| | - Fiorenzo Conti
- Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Center for Neurobiology of Aging, IRCCS INRCA, Ancona, Italy.
| |
Collapse
|
|
18
|
Spoto G, Di Rosa G, Nicotera AG. The Impact of Genetics on Cognition: Insights into Cognitive Disorders and Single Nucleotide Polymorphisms. J Pers Med 2024; 14:156. [PMID: 38392589 PMCID: PMC10889941 DOI: 10.3390/jpm14020156] [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: 12/19/2023] [Revised: 01/23/2024] [Accepted: 01/29/2024] [Indexed: 02/24/2024] Open
Abstract
This article explores the complex relationship between genetics and cognition, specifically examining the impact of genetic variants, particularly single nucleotide polymorphisms (SNPs), on cognitive functions and the development of neuropsychiatric disorders. Focusing on neurotransmitter regulation within the prefrontal cortex's dopaminergic circuits, this study emphasizes the role of genes like COMT, PRODH, and DRD in shaping executive functions and influencing conditions such as ADHD and schizophrenia. Additionally, it explores the significance of genetic factors in neurodevelopmental disorders, emphasizing the need for early identification to guide appropriate therapeutic interventions. This article also investigates polymorphisms in the transsulfuration pathway, revealing their association with cognitive impairment diseases. Computational analyses, including machine learning algorithms, are highlighted for their potential in predicting symptom severity in ADHD based on genetic variations. In conclusion, this article underscores the intricate interplay of genetic and environmental factors in shaping cognitive outcomes, providing valuable insights for tailored treatments and a more comprehensive understanding of neuropsychiatric conditions.
Collapse
Affiliation(s)
- Giulia Spoto
- Unit of Child Neurology and Psychiatry, Department of Biomedical Sciences, Dental Sciences & Morphofunctional Imaging, University of Messina, 98125 Messina, Italy
| | - Gabriella Di Rosa
- Unit of Child Neurology and Psychiatry, Department of Biomedical Sciences, Dental Sciences & Morphofunctional Imaging, University of Messina, 98125 Messina, Italy
| | - Antonio Gennaro Nicotera
- Unit of Child Neurology and Psychiatry, Department of Human Pathology of the Adult and Developmental Age "Gaetano Barresi", University of Messina, 98125 Messina, Italy
| |
Collapse
|
|
19
|
Gattuso JJ, Wilson C, Hannan AJ, Renoir T. Acute administration of the NMDA receptor antagonists ketamine and MK-801 reveals dysregulation of glutamatergic signalling and sensorimotor gating in the Sapap3 knockout mouse model of compulsive-like behaviour. Neuropharmacology 2023; 239:109689. [PMID: 37597609 DOI: 10.1016/j.neuropharm.2023.109689] [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: 05/10/2023] [Revised: 07/30/2023] [Accepted: 08/15/2023] [Indexed: 08/21/2023]
Abstract
Obsessive-compulsive disorder (OCD) is characterised by excessive intrusive thoughts that may cause an individual to engage in compulsive behaviours. Frontline pharmacological treatments (i.e., selective serotonin reuptake inhibitors (SSRIs)) leave approximately 40% of patients refractory to treatment. To investigate the possibility of novel pharmacological therapies for OCD, as well as the potential mechanisms underlying its pathology, we used the Sapap3 knockout (KO) mouse model of OCD, which exhibits increased anxiety and compulsive grooming behaviours. Firstly, we investigated whether administration of the NMDA receptor (NMDAR) antagonist ketamine (30 mg/kg), would reduce anxiety and grooming behaviour in Sapap3 KO mice. Anxiety-like behaviour was measured via time spent in the light component of the light-dark box test. Grooming behaviour was recorded and scored in freely moving mice. In line with previous works conducted in older animals (i.e. typically between 6 and 9 months of age), we confirmed here that Sapap3 KO mice exhibit an anxious, compulsive grooming, hypolocomotive and reduced body weight phenotype even at a younger age (i.e., 2-3 months of age). However, we found that acute administration of ketamine did not cause a reduction in anxiety or grooming behaviour. We then investigated in vivo glutamatergic function via the administration of a different NMDAR antagonist, MK-801 (0.25 mg/kg), prior to locomotion and prepulse inhibition assays. We found evidence of altered functional NMDAR activity, as well as sexually dimorphic prepulse inhibition, a measure of sensorimotor gating, in Sapap3 KO mice. These results are suggestive of in vivo glutamatergic dysfunction and their functional consequences, enabling future research to further investigate novel treatments for OCD.
Collapse
Affiliation(s)
- James J Gattuso
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia
| | - Carey Wilson
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia
| | - Anthony J Hannan
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
| | - Thibault Renoir
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia.
| |
Collapse
|
|
20
|
Kamble SR, Dandekar MP. Implication of microbiota gut-brain axis in the manifestation of obsessive-compulsive disorder: Preclinical and clinical evidence. Eur J Pharmacol 2023; 957:176014. [PMID: 37619786 DOI: 10.1016/j.ejphar.2023.176014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 08/26/2023]
Abstract
Recent research has highlighted the key role of gut microbiota in the development of psychiatric disorders. The adverse impact of stress, anxiety, and depression has been well documented on the commensal gut microflora. Thus, therapeutic benefits of gut microbiota-based interventions may not be avoided in central nervous system (CNS) disorders. In this review, we outline the current state of knowledge of gut microbiota with respect to obsessive-compulsive disorder (OCD). We discuss how OCD-generated changes corresponding to the key neurotransmitters, hypothalamic-pituitary-adrenal axis, and immunological and inflammatory pathways are connected with the modifications of the microbiota-gut-brain axis. Notably, administration of few probiotics such as Lactobacillus rhamnosus (ATCC 53103), Lactobacillus helveticus R0052, Bifidobacterium longum R0175, Saccharomyces boulardii, and Lactobacillus casei Shirota imparted positive effects in the management of OCD symptoms. Taken together, we suggest that the gut microbiota-directed therapeutics may open new treatment approaches for the management of OCD.
Collapse
Affiliation(s)
- Sonali R Kamble
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Manoj P Dandekar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
| |
Collapse
|
|
21
|
Verkhratsky A, Butt A, Li B, Illes P, Zorec R, Semyanov A, Tang Y, Sofroniew MV. Astrocytes in human central nervous system diseases: a frontier for new therapies. Signal Transduct Target Ther 2023; 8:396. [PMID: 37828019 PMCID: PMC10570367 DOI: 10.1038/s41392-023-01628-9] [Citation(s) in RCA: 131] [Impact Index Per Article: 65.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 08/15/2023] [Accepted: 08/22/2023] [Indexed: 10/14/2023] Open
Abstract
Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.
Collapse
Affiliation(s)
- Alexei Verkhratsky
- International Joint Research Centre on Purinergic Signalling/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China.
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
- Achucarro Centre for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, LT-01102, Vilnius, Lithuania.
| | - Arthur Butt
- Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | - Baoman Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
| | - Peter Illes
- International Joint Research Centre on Purinergic Signalling/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, 04109, Leipzig, Germany
| | - Robert Zorec
- Celica Biomedical, Lab Cell Engineering, Technology Park, 1000, Ljubljana, Slovenia
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
| | - Alexey Semyanov
- Department of Physiology, Jiaxing University College of Medicine, 314033, Jiaxing, China
| | - Yong Tang
- International Joint Research Centre on Purinergic Signalling/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
- Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, China.
| | - Michael V Sofroniew
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
| |
Collapse
|
|
22
|
Mich JK, Sunil S, Johansen N, Martinez RA, Leytze M, Gore BB, Mahoney JT, Ben-Simon Y, Bishaw Y, Brouner K, Campos J, Canfield R, Casper T, Dee N, Egdorf T, Gary A, Gibson S, Goldy J, Groce EL, Hirschstein D, Loftus L, Lusk N, Malone J, Martin NX, Monet D, Omstead V, Opitz-Araya X, Oster A, Pom CA, Potekhina L, Reding M, Rimorin C, Ruiz A, Sedeño-Cortés AE, Shapovalova NV, Taormina M, Taskin N, Tieu M, Valera Cuevas NJ, Weed N, Way S, Yao Z, McMillen DA, Kunst M, McGraw M, Thyagarajan B, Waters J, Bakken TE, Yao S, Smith KA, Svoboda K, Podgorski K, Kojima Y, Horwitz GD, Zeng H, Daigle TL, Lein ES, Tasic B, Ting JT, Levi BP. Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.20.558718. [PMID: 37790503 PMCID: PMC10542530 DOI: 10.1101/2023.09.20.558718] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and our astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.
Collapse
|
|
23
|
Kotchetkov P, Blakeley N, Lacoste B. Involvement of brain metabolism in neurodevelopmental disorders. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 173:67-113. [PMID: 37993180 DOI: 10.1016/bs.irn.2023.08.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2023]
Abstract
Neurodevelopmental disorders (NDDs) affect a significant portion of the global population and have a substantial social and economic impact worldwide. Most NDDs manifest in early childhood and are characterized by deficits in cognition, communication, social interaction and motor control. Due to a limited understanding of the etiology of NDDs, current treatment options primarily focus on symptom management rather than on curative solutions. Moreover, research on NDDs is problematic due to its reliance on a neurocentric approach. However, recent studies are broadening the scope of research on NDDs, to include dysregulations within a diverse network of brain cell types, including vascular and glial cells. This review aims to summarize studies from the past few decades on potential new contributions to the etiology of NDDs, with a special focus on metabolic signatures of various brain cells. In particular, we aim to convey how the metabolic functions are intimately linked to the onset and/or progression of common NDDs such as autism spectrum disorders, fragile X syndrome, Rett syndrome and Down syndrome.
Collapse
Affiliation(s)
- Pavel Kotchetkov
- Neuroscience Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Nicole Blakeley
- Neuroscience Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Baptiste Lacoste
- Neuroscience Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada.
| |
Collapse
|
|
24
|
Oya M, Matsuoka K, Kubota M, Fujino J, Tei S, Takahata K, Tagai K, Yamamoto Y, Shimada H, Seki C, Itahashi T, Aoki YY, Ohta H, Hashimoto RI, Sugihara G, Obata T, Zhang MR, Suhara T, Nakamura M, Kato N, Takado Y, Takahashi H, Higuchi M. Increased glutamate and glutamine levels and their relationship to astrocytes and dopaminergic transmissions in the brains of adults with autism. Sci Rep 2023; 13:11655. [PMID: 37468523 DOI: 10.1038/s41598-023-38306-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 07/06/2023] [Indexed: 07/21/2023] Open
Abstract
Increased excitatory neuronal tones have been implicated in autism, but its mechanism remains elusive. The amplified glutamate signals may arise from enhanced glutamatergic circuits, which can be affected by astrocyte activation and suppressive signaling of dopamine neurotransmission. We tested this hypothesis using magnetic resonance spectroscopy and positron emission tomography scan with 11C-SCH23390 for dopamine D1 receptors in the anterior cingulate cortex (ACC). We enrolled 18 male adults with high-functioning autism and 20 typically developed (TD) male subjects. The autism group showed elevated glutamate, glutamine, and myo-inositol (mI) levels compared with the TD group (p = 0.045, p = 0.044, p = 0.030, respectively) and a positive correlation between glutamine and mI levels in the ACC (r = 0.54, p = 0.020). In autism and TD groups, ACC D1 receptor radioligand binding was negatively correlated with ACC glutamine levels (r = - 0.55, p = 0.022; r = - 0.58, p = 0.008, respectively). The enhanced glutamate-glutamine metabolism might be due to astroglial activation and the consequent reinforcement of glutamine synthesis in autistic brains. Glutamine synthesis could underly the physiological inhibitory control of dopaminergic D1 receptor signals. Our findings suggest a high neuron excitation-inhibition ratio with astrocytic activation in the etiology of autism.
Collapse
Affiliation(s)
- Masaki Oya
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
- Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Kiwamu Matsuoka
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan.
- Department of Psychiatry, Nara Medical University, Kashihara-shi, Nara, Japan.
| | - Manabu Kubota
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
- Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto-shi, Kyoto, Japan
- Medical Institute of Developmental Disabilities Research, Showa University, Setagaya-ku, Tokyo, Japan
| | - Junya Fujino
- Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Medical Institute of Developmental Disabilities Research, Showa University, Setagaya-ku, Tokyo, Japan
| | - Shisei Tei
- Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto-shi, Kyoto, Japan
- Medical Institute of Developmental Disabilities Research, Showa University, Setagaya-ku, Tokyo, Japan
- Institute of Applied Brain Sciences, Waseda University, Tokorozawa-shi, Saitama, Japan
- School of Human and Social Sciences, Tokyo International University, Kawagoe-shi, Saitama, Japan
| | - Keisuke Takahata
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
- Department of Neuropsychiatry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Kenji Tagai
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
| | - Yasuharu Yamamoto
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
- Department of Neuropsychiatry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Hitoshi Shimada
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
- Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata-shi, Niigata, Japan
| | - Chie Seki
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
| | - Takashi Itahashi
- Medical Institute of Developmental Disabilities Research, Showa University, Setagaya-ku, Tokyo, Japan
| | - Yuta Y Aoki
- Medical Institute of Developmental Disabilities Research, Showa University, Setagaya-ku, Tokyo, Japan
| | - Haruhisa Ohta
- Medical Institute of Developmental Disabilities Research, Showa University, Setagaya-ku, Tokyo, Japan
- Department of Psychiatry, School of Medicine, Showa University, Setagaya-ku, Tokyo, Japan
| | - Ryu-Ichiro Hashimoto
- Medical Institute of Developmental Disabilities Research, Showa University, Setagaya-ku, Tokyo, Japan
- Department of Language Sciences, Graduate School of Humanities, Tokyo Metropolitan University, Hachioji-shi, Tokyo, Japan
| | - Genichi Sugihara
- Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Takayuki Obata
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba-shi, Chiba, Japan
| | - Ming-Rong Zhang
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba-shi, Chiba, Japan
| | - Tetsuya Suhara
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
| | - Motoaki Nakamura
- Medical Institute of Developmental Disabilities Research, Showa University, Setagaya-ku, Tokyo, Japan
- Kanagawa Psychiatric Center, Yokohama-shi, Kanagawa, Japan
| | - Nobumasa Kato
- Medical Institute of Developmental Disabilities Research, Showa University, Setagaya-ku, Tokyo, Japan
| | - Yuhei Takado
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
| | - Hidehiko Takahashi
- Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Center for Brain Integration Research, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Makoto Higuchi
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
| |
Collapse
|
|
25
|
Medina E, Peterson S, Ford K, Singletary K, Peixoto L. Critical periods and Autism Spectrum Disorders, a role for sleep. Neurobiol Sleep Circadian Rhythms 2023; 14:100088. [PMID: 36632570 PMCID: PMC9826922 DOI: 10.1016/j.nbscr.2022.100088] [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: 09/21/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Brain development relies on both experience and genetically defined programs. Time windows where certain brain circuits are particularly receptive to external stimuli, resulting in heightened plasticity, are referred to as "critical periods". Sleep is thought to be essential for normal brain development. Importantly, studies have shown that sleep enhances critical period plasticity and promotes experience-dependent synaptic pruning in the developing mammalian brain. Therefore, normal plasticity during critical periods depends on sleep. Problems falling and staying asleep occur at a higher rate in Autism Spectrum Disorder (ASD) relative to typical development. In this review, we explore the potential link between sleep, critical period plasticity, and ASD. First, we review the importance of critical period plasticity in typical development and the role of sleep in this process. Next, we summarize the evidence linking ASD with deficits in synaptic plasticity in rodent models of high-confidence ASD gene candidates. We then show that the high-confidence rodent models of ASD that show sleep deficits also display plasticity deficits. Given how important sleep is for critical period plasticity, it is essential to understand the connections between synaptic plasticity, sleep, and brain development in ASD. However, studies investigating sleep or plasticity during critical periods in ASD mouse models are lacking. Therefore, we highlight an urgent need to consider developmental trajectory in studies of sleep and plasticity in neurodevelopmental disorders.
Collapse
Affiliation(s)
- Elizabeth Medina
- Department of Translational Medicine and Physiology, Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - Sarah Peterson
- Department of Translational Medicine and Physiology, Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - Kaitlyn Ford
- Department of Translational Medicine and Physiology, Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - Kristan Singletary
- Department of Translational Medicine and Physiology, Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - Lucia Peixoto
- Department of Translational Medicine and Physiology, Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| |
Collapse
|
|
26
|
Sullivan M, Fernandez-Aranda F, Camacho-Barcia L, Harkin A, Macrì S, Mora-Maltas B, Jiménez-Murcia S, O'Leary A, Ottomana AM, Presta M, Slattery D, Scholtz S, Glennon JC. Insulin and Disorders of Behavioural Flexibility. Neurosci Biobehav Rev 2023; 150:105169. [PMID: 37059405 DOI: 10.1016/j.neubiorev.2023.105169] [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: 12/30/2022] [Revised: 04/03/2023] [Accepted: 04/10/2023] [Indexed: 04/16/2023]
Abstract
Behavioural inflexibility is a symptom of neuropsychiatric and neurodegenerative disorders such as Obsessive-Compulsive Disorder, Autism Spectrum Disorder and Alzheimer's Disease, encompassing the maintenance of a behaviour even when no longer appropriate. Recent evidence suggests that insulin signalling has roles apart from its regulation of peripheral metabolism and mediates behaviourally-relevant central nervous system (CNS) functions including behavioural flexibility. Indeed, insulin resistance is reported to generate anxious, perseverative phenotypes in animal models, with the Type 2 diabetes medication metformin proving to be beneficial for disorders including Alzheimer's Disease. Structural and functional neuroimaging studies of Type 2 diabetes patients have highlighted aberrant connectivity in regions governing salience detection, attention, inhibition and memory. As currently available therapeutic strategies feature high rates of resistance, there is an urgent need to better understand the complex aetiology of behaviour and develop improved therapeutics. In this review, we explore the circuitry underlying behavioural flexibility, changes in Type 2 diabetes, the role of insulin in CNS outcomes and mechanisms of insulin involvement across disorders of behavioural inflexibility.
Collapse
Affiliation(s)
- Mairéad Sullivan
- Conway Institute of Biomedical and Biomolecular Research, School of Medicine, University College Dublin, Dublin, Ireland.
| | - Fernando Fernandez-Aranda
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain; Psychoneurobiology of Eating and Addictive Behaviors Group, Neurosciences Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain; Department of Clinical Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Lucía Camacho-Barcia
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain; Psychoneurobiology of Eating and Addictive Behaviors Group, Neurosciences Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain
| | - Andrew Harkin
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Ireland
| | - Simone Macrì
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Bernat Mora-Maltas
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain; Psychoneurobiology of Eating and Addictive Behaviors Group, Neurosciences Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Susana Jiménez-Murcia
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain; Psychoneurobiology of Eating and Addictive Behaviors Group, Neurosciences Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain; Department of Clinical Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Aet O'Leary
- University Hospital Frankfurt, Frankfurt, Germany
| | - Angela Maria Ottomana
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; Neuroscience Unit, Department of Medicine, University of Parma, 43100 Parma, Italy
| | - Martina Presta
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy
| | | | | | - Jeffrey C Glennon
- Conway Institute of Biomedical and Biomolecular Research, School of Medicine, University College Dublin, Dublin, Ireland
| |
Collapse
|
|
27
|
Delepine C, Shih J, Li K, Gaudeaux P, Sur M. Differential Effects of Astrocyte Manipulations on Learned Motor Behavior and Neuronal Ensembles in the Motor Cortex. J Neurosci 2023; 43:2696-2713. [PMID: 36894315 PMCID: PMC10089242 DOI: 10.1523/jneurosci.1982-22.2023] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 01/31/2023] [Accepted: 03/01/2023] [Indexed: 03/11/2023] Open
Abstract
Although motor cortex is crucial for learning precise and reliable movements, whether and how astrocytes contribute to its plasticity and function during motor learning is unknown. Here, we report that astrocyte-specific manipulations in primary motor cortex (M1) during a lever push task alter motor learning and execution, as well as the underlying neuronal population coding. Mice that express decreased levels of the astrocyte glutamate transporter 1 (GLT1) show impaired and variable movement trajectories, whereas mice with increased astrocyte Gq signaling show decreased performance rates, delayed response times, and impaired trajectories. In both groups, which include male and female mice, M1 neurons have altered interneuronal correlations and impaired population representations of task parameters, including response time and movement trajectories. RNA sequencing further supports a role for M1 astrocytes in motor learning and shows changes in astrocytic expression of glutamate transporter genes, GABA transporter genes, and extracellular matrix protein genes in mice that have acquired this learned behavior. Thus, astrocytes coordinate M1 neuronal activity during motor learning, and our results suggest that this contributes to learned movement execution and dexterity through mechanisms that include regulation of neurotransmitter transport and calcium signaling.SIGNIFICANCE STATEMENT We demonstrate for the first time that in the M1 of mice, astrocyte function is critical for coordinating neuronal population activity during motor learning. We demonstrate that knockdown of astrocyte glutamate transporter GLT1 affects specific components of learning, such as smooth trajectory formation. Altering astrocyte calcium signaling by activation of Gq-DREADD upregulates GLT1 and affects other components of learning, such as response rates and reaction times as well as trajectory smoothness. In both manipulations, neuronal activity in motor cortex is dysregulated, but in different ways. Thus, astrocytes have a crucial role in motor learning via their influence on motor cortex neurons, and they do so by mechanisms that include regulation of glutamate transport and calcium signals.
Collapse
Affiliation(s)
- Chloe Delepine
- The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
| | - Jennifer Shih
- The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
| | - Keji Li
- The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
| | - Pierre Gaudeaux
- The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
| | - Mriganka Sur
- The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
- Simons Center for the Social Brain, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
| |
Collapse
|
|
28
|
Lim D, Tapella L, Dematteis G, Talmon M, Genazzani AA. Calcineurin Signalling in Astrocytes: From Pathology to Physiology and Control of Neuronal Functions. Neurochem Res 2023; 48:1077-1090. [PMID: 36083398 PMCID: PMC10030417 DOI: 10.1007/s11064-022-03744-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 07/31/2022] [Accepted: 08/29/2022] [Indexed: 10/14/2022]
Abstract
Calcineurin (CaN), a Ca2+/calmodulin-activated serine/threonine phosphatase, acts as a Ca2+-sensitive switch regulating cellular functions through protein dephosphorylation and activation of gene transcription. In astrocytes, the principal homeostatic cells in the CNS, over-activation of CaN is known to drive pathological transcriptional remodelling, associated with neuroinflammation in diseases such as Alzheimer's disease, epilepsy and brain trauma. Recent reports suggest that, in physiological conditions, the activity of CaN in astrocytes is transcription-independent and is required for maintenance of basal protein synthesis rate and activation of astrocytic Na+/K+ pump thereby contributing to neuronal functions such as neuronal excitability and memory formation. In this contribution we overview the role of Ca2+ and CaN signalling in astroglial pathophysiology focusing on the emerging physiological role of CaN in astrocytes. We propose a model for the context-dependent switch of CaN activity from the post-transcriptional regulation of cell proteostasis in healthy astrocytes to the CaN-dependent transcriptional activation in neuroinflammation-associated diseases.
Collapse
Affiliation(s)
- Dmitry Lim
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Via Bovio 6, 28100, Novara, Italy.
| | - Laura Tapella
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Via Bovio 6, 28100, Novara, Italy
| | - Giulia Dematteis
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Via Bovio 6, 28100, Novara, Italy
| | - Maria Talmon
- Department of Health Sciences, School of Medicine, Università del Piemonte Orientale "Amedeo Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Armando A Genazzani
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Via Bovio 6, 28100, Novara, Italy.
| |
Collapse
|
|
29
|
Conti F, Pietrobon D. Astrocytic Glutamate Transporters and Migraine. Neurochem Res 2023; 48:1167-1179. [PMID: 36583835 DOI: 10.1007/s11064-022-03849-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/07/2022] [Accepted: 12/17/2022] [Indexed: 12/31/2022]
Abstract
Glutamate levels and lifetime in the brain extracellular space are dinamically regulated by a family of Na+- and K+-dependent glutamate transporters, which thereby control numerous brain functions and play a role in numerous neurological and psychiatric diseases. Migraine is a neurological disorder characterized by recurrent attacks of typically throbbing and unilateral headache and by a global dysfunction in multisensory processing. Familial hemiplegic migraine type 2 (FHM2) is a rare monogenic form of migraine with aura caused by loss-of-function mutations in the α2 Na/K ATPase (α2NKA). In the adult brain, this pump is expressed almost exclusively in astrocytes where it is colocalized with glutamate transporters. Knockin mouse models of FHM2 (FHM2 mice) show a reduced density of glutamate transporters in perisynaptic astrocytic processes (mirroring the reduced expression of α2NKA) and a reduced rate of glutamate clearance at cortical synapses during neuronal activity and sensory stimulation. Here we review the migraine-relevant alterations produced by the astrocytic glutamate transport dysfunction in FHM2 mice and their underlying mechanisms, in particular regarding the enhanced brain susceptibility to cortical spreading depression (the phenomenon that underlies migraine aura and can also initiate the headache mechanisms) and the enhanced algesic response to a migraine trigger.
Collapse
Affiliation(s)
- Fiorenzo Conti
- Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy.
- Center for Neurobiology of Aging, IRCCS INRCA, Ancona, Italy.
| | - Daniela Pietrobon
- Department of Biomedical Sciences and Padova Neuroscience Center (PNC), University of Padova, 35131, Padua, Italy.
- CNR Institute of Neuroscience, 35131, Padua, Italy.
| |
Collapse
|
|
30
|
Zohny SM, Habib MZ, Mohamad MI, Elayat WM, Elhossiny RM, El-Salam MFA, Hassan GAM, Aboul-Fotouh S. Memantine/Aripiprazole Combination Alleviates Cognitive Dysfunction in Valproic Acid Rat Model of Autism: Hippocampal CREB/BDNF Signaling and Glutamate Homeostasis. Neurotherapeutics 2023; 20:464-483. [PMID: 36918475 PMCID: PMC10121975 DOI: 10.1007/s13311-023-01360-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2023] [Indexed: 03/15/2023] Open
Abstract
Significant efforts are increasingly directed towards identifying novel therapeutic targets for autism spectrum disorder (ASD) with a rising role of aberrant glutamatergic transmission in the pathogenesis of ASD-associated cellular and behavioral deficits. This study aimed at investigating the role of chronic memantine (20 mg/kg/day) and aripiprazole (3 mg/kg/day) combination therapy in the management of prenatal sodium valproate (VPA)-induced autistic-like/cognitive deficits in male Wistar rats. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like behaviors in their offspring. Prenatal VPA induced autistic-like symptoms (decreased social interaction and the appearance of stereotyped behavior) with deficits in spatial learning (in Morris water maze) and cognitive flexibility (in the attentional set-shifting task) in addition to decreased hippocampal protein levels of phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and gene expression of glutamate transporter-1 (Glt-1) with a decline in GABA/glutamate ratio (both measured by HPLC). These were accompanied by the appearance of numerous neurofibrillary tangles (NFTs) with enhanced apoptosis in hippocampal sections. Memantine/aripiprazole combination increased the protein levels of p-CREB, BDNF, and Glt-1 gene expression with restoration of GABA/glutamate balance, attenuation of VPA-induced neurodegenerative changes and autistic-like symptoms, and improvement of cognitive performance. This study draws attention to the favorable cognitive effects of memantine/aripiprazole combination in autistic subjects which could be mediated via enhancing CREB/BDNF signaling with increased expression of astrocytic Glt-1 and restoration of GABA/glutamate balance, leading to inhibition of hippocampal NFTs formation and neuronal apoptosis.
Collapse
Affiliation(s)
- Sohir M Zohny
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, 11566, Egypt
| | - Mohamed Z Habib
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
| | - Magda I Mohamad
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Wael M Elayat
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Reham M Elhossiny
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Ghada A M Hassan
- Neuropsychiatry Department, Faculty of Medicine, Galala University, Al Galala, Egypt
- Neuropsychiatry Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sawsan Aboul-Fotouh
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, 11566, Egypt
- Clinical Pharmacology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
31
|
Goswami N, Aleem M, Manda K. Intranasal (2R, 6R)-hydroxynorketamine for acute pain: Behavioural and neurophysiological safety analysis in mice. Clin Exp Pharmacol Physiol 2023; 50:169-177. [PMID: 36371631 DOI: 10.1111/1440-1681.13737] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 10/12/2022] [Accepted: 11/09/2022] [Indexed: 11/14/2022]
Abstract
Ketamine is known for its antinociceptive effect and is also used for treatment-resistant depression. However, the efficacy and safety of (2R, 6R)-hydroxynorketamine (HNK), a ketamine metabolite has been sparingly investigated for acute pain management. The current study aims at investigating the antinociceptive effect of intranasal (2R, 6R)-HNK using pre-clinical models of acute pain. Additionally, the behavioural and neurophysiological safety analyses were carried out for the effective time window. Antinociceptive efficacy of (2R, 6R)-HNK was evaluated using the hot plate test and Hargreaves' plantar test. The formalin test was carried out in both the acute and tonic phases. The neurophysiological and behavioural safety analyses were carried out separately for the haemodynamic function, cortical electroencephalography (EEG), and spontaneous behavioural functions. Analgesic effect of (2R, 6R)-HNK was evident by a significant increase in paw-withdrawal latency in both Hargreaves' and hot plate tests. Additionally, the (2R, 6R)-HNK showed a significant ameliorative effect on pain-related behaviour in the second phase of the formalin test. (2R, 6R)-HNK exhibited an anxiolytic effect without causing any significant changes in locomotor activity and haemodynamic parameters. Power spectral density (PSD) analysis of electroencephalogram revealed no significant changes except a comparative increase in the gamma band range. Both the locomotor functions in the open field test and the PSD value of delta wave indicated no sedative effect at the given dose of (2R, 6R)-HNK. The results demonstrated the pain-alleviating effect of (2R, 6R)-HNK without compromising the neurophysiological and behavioural function. Therefore, intranasal (2R, 6R)-HNK is suggested as a safe candidate for further clinical study in the management of acute pain.
Collapse
Affiliation(s)
- Nidhi Goswami
- Division of Behavioral Neuroscience, Institute of Nuclear Medicine & Allied Sciences, Delhi, India
| | - Mohd Aleem
- Division of Behavioral Neuroscience, Institute of Nuclear Medicine & Allied Sciences, Delhi, India
| | - Kailash Manda
- Division of Behavioral Neuroscience, Institute of Nuclear Medicine & Allied Sciences, Delhi, India
| |
Collapse
|
|
32
|
Xiong Y, Chen J, Li Y. Microglia and astrocytes underlie neuroinflammation and synaptic susceptibility in autism spectrum disorder. Front Neurosci 2023; 17:1125428. [PMID: 37021129 PMCID: PMC10067592 DOI: 10.3389/fnins.2023.1125428] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/03/2023] [Indexed: 04/07/2023] Open
Abstract
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with onset in childhood. The mechanisms underlying ASD are unclear. In recent years, the role of microglia and astrocytes in ASD has received increasing attention. Microglia prune the synapses or respond to injury by sequestrating the injury site and expressing inflammatory cytokines. Astrocytes maintain homeostasis in the brain microenvironment through the uptake of ions and neurotransmitters. However, the molecular link between ASD and microglia and, or astrocytes remains unknown. Previous research has shown the significant role of microglia and astrocytes in ASD, with reports of increased numbers of reactive microglia and astrocytes in postmortem tissues and animal models of ASD. Therefore, an enhanced understanding of the roles of microglia and astrocytes in ASD is essential for developing effective therapies. This review aimed to summarize the functions of microglia and astrocytes and their contributions to ASD.
Collapse
|
|
33
|
Alijanpour S, Miryounesi M, Ghafouri-Fard S. The role of excitatory amino acid transporter 2 (EAAT2) in epilepsy and other neurological disorders. Metab Brain Dis 2023; 38:1-16. [PMID: 36173507 DOI: 10.1007/s11011-022-01091-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/15/2022] [Indexed: 02/03/2023]
Abstract
Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). Excitatory amino acid transporters (EAATs) have important roles in the uptake of glutamate and termination of glutamatergic transmission. Up to now, five EAAT isoforms (EAAT1-5) have been identified in mammals. The main focus of this review is EAAT2. This protein has an important role in the pathoetiology of epilepsy. De novo dominant mutations, as well as inherited recessive mutation in this gene, have been associated with epilepsy. Moreover, dysregulation of this protein is implicated in a range of neurological diseases, namely amyotrophic lateral sclerosis, alzheimer's disease, parkinson's disease, schizophrenia, epilepsy, and autism. In this review, we summarize the role of EAAT2 in epilepsy and other neurological disorders, then provide an overview of the therapeutic modulation of this protein.
Collapse
Affiliation(s)
- Sahar Alijanpour
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Miryounesi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
34
|
Zhang X, Liu S, Liu X, Wang J. Inhibiting silence information regulator 2 and glutaminase in the amygdala can improve social behavior in autistic rats. Zhejiang Da Xue Xue Bao Yi Xue Ban 2022; 51:707-715. [PMID: 36915976 PMCID: PMC10262010 DOI: 10.3724/zdxbyxb-2022-0183] [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: 04/29/2022] [Accepted: 09/30/2022] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To investigate the underlying molecular mechanisms by which silence information regulator (SIRT) 2 and glutaminase (GLS) in the amygdala regulate social behaviors in autistic rats. METHODS Rat models of autism were established by maternal sodium valproic acid (VPA) exposure in wild-type rats and SIRT2-knockout ( SIRT2 -/-) rats. Glutamate (Glu) content, brain weight, and expression levels of SIRT2, GLS proteins and apoptosis-associated proteins in rat amygdala at different developmental stages were examined, and the social behaviors of VPA rats were assessed by a three-chamber test. Then, lentiviral overexpression or interference vectors of GLS were injected into the amygdala of VPA rats. Brain weight, Glu content and expression level of GLS protein were measured, and the social behaviors assessed. RESULTS Brain weight, amygdala Glu content and the levels of SIRT2, GLS protein and pro-apoptotic protein caspase-3 in the amygdala were increased in VPA rats, while the level of anti-apoptotic protein Bcl-2 was decreased (all P<0.01). Compared with the wild-type rats, SIRT2 -/- rats displayed decreased expression of SIRT2 and GLS proteins in the amygdala, reduced Glu content, and improved social dysfunction (all P<0.01). Overexpression of GLS increased brain weight and Glu content, and aggravated social dysfunction in VPA rats (all P<0.01). Knockdown of GLS decreased brain weight and Glu content, and improved social dysfunction in VPA rats (all P<0.01). CONCLUSIONS The glutamate circulatory system in the amygdala of VPA induced autistic rats is abnormal. This is associated with the upregulation of SIRT2 expression and its induced increase of GLS production; knocking out SIRT2 gene or inhibiting the expression of GLS is helpful in maintaining the balanced glutamate cycle and in improving the social behavior disorder of rats.
Collapse
Affiliation(s)
- Xiaoxia Zhang
- 1. Children's Hospital, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Shizhang Liu
- 2. Department of Orthopedics, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Xiaomei Liu
- 3. Nursing Department, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Jieying Wang
- 1. Children's Hospital, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| |
Collapse
|
|
35
|
Kilb W, Kirischuk S. GABA Release from Astrocytes in Health and Disease. Int J Mol Sci 2022; 23:ijms232415859. [PMID: 36555501 PMCID: PMC9784789 DOI: 10.3390/ijms232415859] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/06/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022] Open
Abstract
Astrocytes are the most abundant glial cells in the central nervous system (CNS) mediating a variety of homeostatic functions, such as spatial K+ buffering or neurotransmitter reuptake. In addition, astrocytes are capable of releasing several biologically active substances, including glutamate and GABA. Astrocyte-mediated GABA release has been a matter of debate because the expression level of the main GABA synthesizing enzyme glutamate decarboxylase is quite low in astrocytes, suggesting that low intracellular GABA concentration ([GABA]i) might be insufficient to support a non-vesicular GABA release. However, recent studies demonstrated that, at least in some regions of the CNS, [GABA]i in astrocytes might reach several millimoles both under physiological and especially pathophysiological conditions, thereby enabling GABA release from astrocytes via GABA-permeable anion channels and/or via GABA transporters operating in reverse mode. In this review, we summarize experimental data supporting both forms of GABA release from astrocytes in health and disease, paying special attention to possible feedback mechanisms that might govern the fine-tuning of astrocytic GABA release and, in turn, the tonic GABAA receptor-mediated inhibition in the CNS.
Collapse
|
|
36
|
Alibek K, Niyazmetova L, Farmer S, Isakov T. Persistent Inflammation Initiated by TORCH Infections and Dysbiotic Microbiome in Autism Spectrum Disorders: A Prospect for Future Interventions. RESEARCH IDEAS AND OUTCOMES 2022. [DOI: 10.3897/rio.8.e91179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Autism spectrum disorders (ASD) are a range of neurodevelopmental conditions that are clinically present early in childhood with the symptoms of social withdrawal and repetitive behavior. Despite an extensive research on ASD, no commonly accepted theory on the disease etiology exists. Hence, we reviewed several scientific publications, including reviews, preclinical and clinical investigations, and published hypotheses to analyze various opinions on the nature and cause of the disorder. Many studies suggest that infections and inflammation during pregnancy play a significant role in genetic and epigenetic changes in the developing fetus, resulting in an autistic phenotype in a child. Still, there is a lack of comprehensive literature about the multitude of autism inducing factors. Therefore, this article reviews and discusses available scientific evidence on the roles of viral, bacterial, fungal, and parasitic infections, overactivation of the immune system, and intestinal microflora in the pathogenesis and clinical manifestation of ASD. The overview of the scientific publications, including our own studies, suggests that TORCH infections, imbalanced microbiome, and persistent inflammation are significantly associated with the disruption of the social domain in ASD children. The ASD-related changes begin prenatally as maternal-to-fetal immune activation triggered by infection. It results in continuous low-grade inflammation and oxidative stress in a fetus, causing germline and somatic genetic changes in the developing brain and the establishment of the dysregulated immune system. These changes and dysregulations result in central and peripheral nervous systems dysfunctions as well as other comorbid conditions found in autistic children.
Collapse
|
|
37
|
Petrelli F, Zehnder T, Laugeray A, Mondoloni S, Calì C, Pucci L, Molinero Perez A, Bondiolotti BM, De Oliveira Figueiredo E, Dallerac G, Déglon N, Giros B, Magrassi L, Mothet JP, Mameli M, Simmler LD, Bezzi P. Disruption of Astrocyte-Dependent Dopamine Control in the Developing Medial Prefrontal Cortex Leads to Excessive Grooming in Mice. Biol Psychiatry 2022; 93:966-975. [PMID: 36958999 DOI: 10.1016/j.biopsych.2022.11.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 10/21/2022] [Accepted: 11/04/2022] [Indexed: 12/07/2022]
Abstract
BACKGROUND Astrocytes control synaptic activity by modulating perisynaptic concentrations of ions and neurotransmitters including dopamine (DA) and, as such, could be involved in the modulating aspects of mammalian behavior. METHODS We produced a conditional deletion of the vesicular monoamine transporter 2 (VMAT2) specifically in astrocytes (aVMTA2cKO mice) and studied the effects of the lack of VMAT2 in prefrontal cortex (PFC) astrocytes on the regulation of DA levels, PFC circuit functions, and behavioral processes. RESULTS We found a significant reduction of medial PFC (mPFC) DA levels and excessive grooming and compulsive repetitive behaviors in aVMAT2cKO mice. The mice also developed a synaptic pathology, expressed through increased relative AMPA versus NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioral and synaptic phenotypes were rescued by re-expression of mPFC VMAT2 and L-DOPA treatment, showing that the deficits were driven by mPFC astrocytes that are critically involved in developmental DA homeostasis. By analyzing human tissue samples, we found that VMAT2 is expressed in human PFC astrocytes, corroborating the potential translational relevance of our observations in mice. CONCLUSIONS Our study shows that impairment of the astrocytic control of DA in the mPFC leads to symptoms resembling obsessive-compulsive spectrum disorders such as trichotillomania and has a profound impact on circuit function and behaviors.
Collapse
Affiliation(s)
- Francesco Petrelli
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Tamara Zehnder
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Anthony Laugeray
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Sarah Mondoloni
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Corrado Calì
- Department of Neuroscience, University of Torino, Torino, Italy
| | - Luca Pucci
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Alicia Molinero Perez
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | | | | | - Glenn Dallerac
- Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille Université UMR7286 CNRS, Marseille, France
| | - Nicole Déglon
- Neurosciences Research Center, Laboratory of Neurotherapies and Neuromodulation, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Bruno Giros
- Department of Psychiatry, Douglas Hospital Research Center, McGill University, Montreal, Quebec, Canada
| | - Lorenzo Magrassi
- Neurosurgery, Dipartimento di Scienze Clinico-Chirurgiche e Pediatriche, Università degli Studi di Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Jean-Pierre Mothet
- Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille Université UMR7286 CNRS, Marseille, France; "Biophotonics and Synapse Physiopathology" Team, UMR9188 CNRS - ENS Paris Saclay, Orsay, France
| | - Manuel Mameli
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Linda D Simmler
- Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland.
| | - Paola Bezzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
| |
Collapse
|
|
38
|
Xi L, Ji X, Ji W, Yang Y, Zhang Y, Long H. Jing-an oral liquid alleviates Tourette syndrome via the NMDAR/MAPK/CREB pathway in vivo and in vitro. PHARMACEUTICAL BIOLOGY 2022; 60:1790-1800. [PMID: 36102587 PMCID: PMC9487928 DOI: 10.1080/13880209.2022.2116056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 07/01/2022] [Accepted: 08/13/2022] [Indexed: 06/15/2023]
Abstract
CONTEXT Jing-an oral liquid (JA) is a Chinese herbal formula used in the treatment of Tourette syndrome (TS); however, its mechanism is unclear. OBJECTIVE To investigate the effects of JA on amino acid neurotransmitters and microglia activation in vivo and in vitro. MATERIALS AND METHODS Sixty male Sprague-Dawley rats were divided into a control group and 5 TS groups. TS was induced in rats with intraperitoneal injection of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1 mg/kg) and in BV2 cells with lipopolysaccharide. Control and model rats were administered saline, whereas treatment groups were administered JA (5.18, 10.36, or 20.72 g/kg) or tiapride (a benzamide, 23.5 mg/kg) by gavage once daily for 21 days. Stereotypic behaviour was tested. The levels of N-methyl-d-aspartate receptor (NMDAR)/mitogen-activated protein kinase/cAMP response element-binding protein (CREB)-related proteins in striatum and BV2 cells were measured via western blots. CD11b and IBa1 levels were also measured. Ultra-high-performance liquid-chromatography was used to determine γ-aminobutyric acid (GABA), glutamic acid (Glu), and aspartic acid (ASP) levels. RESULTS JA markedly alleviated the stereotype behaviour (25.92 ± 0.35 to 13.78 ± 0.47) in rats. It also increased NMDAR1 (0.48 ± 0.09 to 0.67 ± 0.08; 0.54 ± 0.07 to 1.19 ± 0.18) expression and down-regulated the expression of p-ERK, p-JNK, p-P38, and p-CREB in BV2 cells and rat striatum. Additionally, Glu, ASP, GABA, CD11b, and IBa1 levels were significantly decreased by JA. DISCUSSION AND CONCLUSIONS JA suppressed microglia activation and regulated the levels of amino acid neurotransmitters, indicating that it could be a promising therapeutic agent for TS.
Collapse
Affiliation(s)
- Leying Xi
- Department of Pediatrics, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
- Department of Pediatric, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xixi Ji
- Department of Pediatrics, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
- Department of Pediatric, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenxiu Ji
- Department of Pediatrics, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
- Department of Pediatric, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yue’e Yang
- Department of Pediatrics, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Yajie Zhang
- Central Laboratory, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
- Clinical Biobank of Nanjing Hospital of Chinese Medicine, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongyan Long
- Department of Pediatrics, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
- Department of Pediatric, Nanjing University of Chinese Medicine, Nanjing, China
- Central Laboratory, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
- Clinical Biobank of Nanjing Hospital of Chinese Medicine, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| |
Collapse
|
|
39
|
Huang W, Wang Z, Wang G, Li K, Jin Y, Zhao F. Disturbance of glutamate metabolism and inhibition of CaM-CaMKII-CREB signaling pathway in the hippocampus of mice induced by 1,2-dichloroethane exposure. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 310:119813. [PMID: 35868470 DOI: 10.1016/j.envpol.2022.119813] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/15/2022] [Accepted: 07/16/2022] [Indexed: 06/15/2023]
Abstract
1,2-Dichloroethane (1,2-DCE) is a highly toxic neurotoxicity, and the brain tissue is the main target organ. At present, long-term exposure to 1,2-DCE has been shown to cause cognitive dysfunction in some studies, but the mechanism is not clear. The results of this study showed that long-term 1,2-DCE exposure decreased learning and memory abilities in mice and impaired the structure and morphology of neurons in the hippocampal region. Moreover, except for the mRNA level of PAG, the enzymatic activities and protein levels of GS and PAG, as well as the mRNA level of GS were inhibited. With increasing dose of exposure, the protein and mRNA expression of GLAST and GLT-1 also decreased. Contrarily, there were protein and mRNA expression upregulation of GluN1, GluN2A and GluN2B in the hippocampus, as well as increased levels of extracellular Glu and intracellular Ca2+. In addition, 1,2-DCE exposure also downregulated the protein expression levels of CaM, CaMKII and CREB. Taken together, our results suggest that long-term 1,2-DCE exposure impairs the learning and memory capacity in mice, which may be attributed to the disruption of Glu metabolism and the inhibition of CaM- CaMKII-CREB signaling pathway in the hippocampus.
Collapse
Affiliation(s)
- Weiyu Huang
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Zijiang Wang
- Liaoning Provincial Center for Disease Control and Prevention, Shenyang, Liaoning, People's Republic of China
| | - Gaoyang Wang
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Kunyang Li
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Yaping Jin
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Fenghong Zhao
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China.
| |
Collapse
|
|
40
|
Glorie D, Verhaeghe J, Miranda A, De Lombaerde S, Stroobants S, Staelens S. Quantification of Metabotropic Glutamate Receptor 5 Availability With Both [ 11C]ABP688 and [ 18F]FPEB Positron Emission Tomography in the Sapap3 Knockout Mouse Model for Obsessive-Compulsive-like Behavior. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2022; 7:607-615. [PMID: 34856382 DOI: 10.1016/j.bpsc.2021.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 11/17/2021] [Accepted: 11/20/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND This study provides a first direct comparison between positron emission tomography radioligands targeting the allosteric site of the metabotropic glutamate receptor 5 (mGluR5): [11C]ABP688 and [18F]FPEB. A blocking paradigm was set up to substantiate the common binding site of both radioligands. Second, both radioligands were applied in Sapap3 knockout (KO) mice showing compulsive-like behavior characterized by a lower in vivo mGluR5 availability. METHODS First, wild-type mice (n = 7) received four position emission tomography/computed tomography scans: a [11C]ABP688 scan, a [18F]FPEB scan, and two blocking scans using cold FPEB and cold ABP688, respectively. A second experiment compared both radioligands in wild-type (n = 7) and KO (n = 10) mice. The simplified reference tissue model was used to calculate the nondisplaceable binding potential representing the in vivo availability of mGluR5 in the brain. RESULTS Using cold FPEB as a blocking compound for [11C]ABP688 micro-positron emission tomography and vice versa, we observed averaged global reductions in mGluR5 availability of circa 98% for [11C]ABP688 and 82%-96% for [18F]FPEB. For KOs, the [11C]ABP688 nondisplaceable binding potential was on average 25% lower compared with wild-type control mice (p < .0001-.001), while this was about 17% for [18F]FPEB (p < .05). CONCLUSIONS The current findings substantiate a common binding site and suggest a strong relationship between mGluR5 availability levels measured with both radioligands. In Sapap3 KO mice, a reduced mGluR5 availability could therefore be demonstrated with both radioligands. With [11C]ABP688, higher significance levels were achieved in more brain regions. These findings suggest [11C]ABP688 as a preferable radiotracer to quantify mGluR5 availability, as exemplified here in a model for compulsive-like behavior.
Collapse
Affiliation(s)
- Dorien Glorie
- Molecular Imaging Center Antwerp, University of Antwerp, Wilrijk, Belgium
| | - Jeroen Verhaeghe
- Molecular Imaging Center Antwerp, University of Antwerp, Wilrijk, Belgium
| | - Alan Miranda
- Molecular Imaging Center Antwerp, University of Antwerp, Wilrijk, Belgium
| | - Stef De Lombaerde
- Molecular Imaging Center Antwerp, University of Antwerp, Wilrijk, Belgium; Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium
| | - Sigrid Stroobants
- Molecular Imaging Center Antwerp, University of Antwerp, Wilrijk, Belgium; Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium
| | - Steven Staelens
- Molecular Imaging Center Antwerp, University of Antwerp, Wilrijk, Belgium.
| |
Collapse
|
|
41
|
Rose JK, Butterfield M, Liang J, Parvand M, Lin CHS, Rankin CH. Neuroligin Plays a Role in Ethanol-Induced Disruption of Memory and Corresponding Modulation of Glutamate Receptor Expression. Front Behav Neurosci 2022; 16:908630. [PMID: 35722190 PMCID: PMC9204643 DOI: 10.3389/fnbeh.2022.908630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/04/2022] [Indexed: 11/13/2022] Open
Abstract
Exposure to alcohol causes deficits in long-term memory formation across species. Using a long-term habituation memory assay in Caenorhabditis elegans, the effects of ethanol on long-term memory (> 24 h) for habituation were investigated. An impairment in long-term memory was observed when animals were trained in the presence of ethanol. Cues of internal state or training context during testing did not restore memory. Ethanol exposure during training also interfered with the downregulation of AMPA/KA-type glutamate receptor subunit (GLR-1) punctal expression previously associated with long-term memory for habituation in C. elegans. Interestingly, ethanol exposure alone had the opposite effect, increasing GLR-1::GFP punctal expression. Worms with a mutation in the C. elegans ortholog of vertebrate neuroligins (nlg-1) were resistant to the effects of ethanol on memory, as they displayed both GLR-1::GFP downregulation and long-term memory for habituation after training in the presence of ethanol. These findings provide insights into the molecular mechanisms through which alcohol consumption impacts memory.
Collapse
|
|
42
|
McGrath T, Baskerville R, Rogero M, Castell L. Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases. Nutrients 2022; 14:nu14050917. [PMID: 35267893 PMCID: PMC8912368 DOI: 10.3390/nu14050917] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/06/2022] [Accepted: 02/15/2022] [Indexed: 02/04/2023] Open
Abstract
The monoamine model of depression has long formed the basis of drug development but fails to explain treatment resistance or associations with stress or inflammation. Recent animal research, clinical trials of ketamine (a glutamate receptor antagonist), neuroimaging research, and microbiome studies provide increasing evidence of glutamatergic dysfunction in depression and other disorders. Glutamatergic involvement across diverse neuropathologies including psychoses, neurodevelopmental, neurodegenerative conditions, and brain injury forms the rationale for this review. Glutamate is the brain's principal excitatory neurotransmitter (NT), a metabolic and synthesis substrate, and an immune mediator. These overlapping roles and multiple glutamate NT receptor types complicate research into glutamate neurotransmission. The glutamate microcircuit comprises excitatory glutamatergic neurons, astrocytes controlling synaptic space levels, through glutamate reuptake, and inhibitory GABA interneurons. Astroglia generate and respond to inflammatory mediators. Glutamatergic microcircuits also act at the brain/body interface via the microbiome, kynurenine pathway, and hypothalamus-pituitary-adrenal axis. Disruption of excitatory/inhibitory homeostasis causing neuro-excitotoxicity, with neuronal impairment, causes depression and cognition symptoms via limbic and prefrontal regions, respectively. Persistent dysfunction reduces neuronal plasticity and growth causing neuronal death and tissue atrophy in neurodegenerative diseases. A conceptual overview of brain glutamatergic activity and peripheral interfacing is presented, including the common mechanisms that diverse diseases share when glutamate homeostasis is disrupted.
Collapse
Affiliation(s)
- Thomas McGrath
- Green Templeton College, University of Oxford, Oxford OX2 6HG, UK; (T.M.); (L.C.)
| | - Richard Baskerville
- Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK
- Correspondence:
| | - Marcelo Rogero
- School of Public Health, University of Sao Paulo, Sao Paulo 01246-904, Brazil;
| | - Linda Castell
- Green Templeton College, University of Oxford, Oxford OX2 6HG, UK; (T.M.); (L.C.)
| |
Collapse
|
|
43
|
Rimmele TS, Li S, Andersen JV, Westi EW, Rotenberg A, Wang J, Aldana BI, Selkoe DJ, Aoki CJ, Dulla CG, Rosenberg PA. Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus. Front Cell Neurosci 2022; 15:788262. [PMID: 35035352 PMCID: PMC8752461 DOI: 10.3389/fncel.2021.788262] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/08/2021] [Indexed: 12/26/2022] Open
Abstract
GLT-1, the major glutamate transporter in the mammalian central nervous system, is expressed in presynaptic terminals that use glutamate as a neurotransmitter, in addition to astrocytes. It is widely assumed that glutamate homeostasis is regulated primarily by glutamate transporters expressed in astrocytes, leaving the function of GLT-1 in neurons relatively unexplored. We generated conditional GLT-1 knockout (KO) mouse lines to understand the cell-specific functions of GLT-1. We found that stimulus-evoked field extracellular postsynaptic potentials (fEPSPs) recorded in the CA1 region of the hippocampus were normal in the astrocytic GLT-1 KO but were reduced and often absent in the neuronal GLT-1 KO at 40 weeks. The failure of fEPSP generation in the neuronal GLT-1 KO was also observed in slices from 20 weeks old mice but not consistently from 10 weeks old mice. Using an extracellular FRET-based glutamate sensor, we found no difference in stimulus-evoked glutamate accumulation in the neuronal GLT-1 KO, suggesting a postsynaptic cause of the transmission failure. We hypothesized that excitotoxicity underlies the failure of functional recovery of slices from the neuronal GLT-1 KO. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist MK801, when present in the ACSF during the recovery period following cutting of slices, promoted full restoration of fEPSP generation. The inclusion of an enzymatic glutamate scavenging system in the ACSF conferred partial protection. Excitotoxicity might be due to excess release or accumulation of excitatory amino acids, or to metabolic perturbation resulting in increased vulnerability to NMDA receptor activation. Previous studies have demonstrated a defect in the utilization of glutamate by synaptic mitochondria and aspartate production in the synGLT-1 KO in vivo, and we found evidence for similar metabolic perturbations in the slice preparation. In addition, mitochondrial cristae density was higher in synaptic mitochondria in the CA1 region in 20–25 weeks old synGLT-1 KO mice in the CA1 region, suggesting compensation for loss of axon terminal GLT-1 by increased mitochondrial efficiency. These data suggest that GLT-1 expressed in presynaptic terminals serves an important role in the regulation of vulnerability to excitotoxicity, and this regulation may be related to the metabolic role of GLT-1 expressed in glutamatergic axon terminals.
Collapse
Affiliation(s)
- Theresa S Rimmele
- Department of Neurology and the F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, United States
| | - Shaomin Li
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Jens Velde Andersen
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Emil W Westi
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Alexander Rotenberg
- Department of Neurology and the F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, United States.,Program in Neuroscience, Harvard Medical School, Boston, MA, United States
| | - Jianlin Wang
- Department of Neurology and the F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, United States
| | - Blanca Irene Aldana
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Dennis J Selkoe
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Chiye J Aoki
- Center for Neural Science, New York University, NY, United States.,Neuroscience Institute NYU Langone Medical Center, NY, United States
| | - Chris G Dulla
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA, United States
| | - Paul Allen Rosenberg
- Department of Neurology and the F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, United States.,Program in Neuroscience, Harvard Medical School, Boston, MA, United States
| |
Collapse
|
|
44
|
Danbolt NC, López-Corcuera B, Zhou Y. Reconstitution of GABA, Glycine and Glutamate Transporters. Neurochem Res 2022; 47:85-110. [PMID: 33905037 PMCID: PMC8763731 DOI: 10.1007/s11064-021-03331-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/13/2021] [Accepted: 04/15/2021] [Indexed: 10/25/2022]
Abstract
In contrast to water soluble enzymes which can be purified and studied while in solution, studies of solute carrier (transporter) proteins require both that the protein of interest is situated in a phospholipid membrane and that this membrane forms a closed compartment. An additional challenge to the study of transporter proteins has been that the transport depends on the transmembrane electrochemical gradients. Baruch I. Kanner understood this early on and first developed techniques for studying plasma membrane vesicles. This advanced the field in that the experimenter could control the electrochemical gradients. Kanner, however, did not stop there, but started to solubilize the membranes so that the transporter proteins were taken out of their natural environment. In order to study them, Kanner then had to find a way to reconstitute them (reinsert them into phospholipid membranes). The scope of the present review is both to describe the reconstitution method in full detail as that has never been done, and also to reveal the scientific impact that this method has had. Kanner's later work is not reviewed here although that also deserves a review because it too has had a huge impact.
Collapse
Affiliation(s)
- Niels Christian Danbolt
- Neurotransporter Group, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway.
| | - Beatriz López-Corcuera
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
- IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
| | - Yun Zhou
- Neurotransporter Group, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway
| |
Collapse
|
|
45
|
Iwasaki K, Hotta-Hirashima N, Funato H, Yanagisawa M. Protocol for sleep analysis in the brain of genetically modified adult mice. STAR Protoc 2021; 2:100982. [PMID: 34917975 PMCID: PMC8666358 DOI: 10.1016/j.xpro.2021.100982] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Elucidating the molecular pathways that regulate animal behavior such as sleep is essential for understanding how the brain works. However, to examine how a certain functional domain of protein is involved in animal behavior is challenging. Here, we present a protocol for inducing endogenous protein that lacks a specific functional domain using Cre-mediated allele modification in neurons followed by electroencephalogram/electromyogram (EEG/EMG) recording to study the role of kinases in sleep. This strategy is applicable to other gene targets or behaviors. For complete details on the use and execution of this protocol, please refer to Iwasaki et al. (2021).
Collapse
Affiliation(s)
- Kanako Iwasaki
- International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Noriko Hotta-Hirashima
- International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.,Department of Anatomy, Graduate School of Medicine, Toho University, Ota-ku, Tokyo 951-8585, Japan
| | - Hiromasa Funato
- International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.,Department of Anatomy, Graduate School of Medicine, Toho University, Ota-ku, Tokyo 951-8585, Japan
| | - Masashi Yanagisawa
- International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.,Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
| |
Collapse
|
|
46
|
Abstract
Astroglia are key regulators of synaptic function, playing central roles in homeostatic ion buffering, energy dynamics, transmitter uptake, maintenance of neurotransmitter pools, and regulation of synaptic plasticity through release of neuroactive chemicals. Given the myriad of crucial homeostatic and signaling functions attributed to astrocytes and the variety of neurotransmitter receptors expressed by astroglia, they serve as prime cellular candidates for establishing maladaptive synaptic plasticity following drug exposure. Initial studies on astroglia and addiction have placed drug-mediated disruptions in the homeostatic regulation of glutamate as a central aspect of relapse vulnerability. However, the generation of sophisticated tools to study and manipulate astroglia have proven that the interaction between addictive substances, astroglia, and relapse-relevant synaptic plasticity extends far beyond the homeostatic regulation of glutamate. Here we present astroglial systems impacted by drug exposure and discuss how changes in astroglial biology contribute to addiction biology.
Collapse
|
|
47
|
Tanaka K. Astroglia and Obsessive Compulsive Disorder. ADVANCES IN NEUROBIOLOGY 2021; 26:139-149. [PMID: 34888834 DOI: 10.1007/978-3-030-77375-5_7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Obsessive compulsive disorder (OCD) has a prevalence rate of 1-3% in the general population and has been ranked as one of the top ten leading causes of illness-related disability (American Psychiatric Association 2013; Kessler et al. 2005). OCD is characterized by persistent intrusive thoughts (obsessions) and repetitive behaviors (compulsions) (Leckman et al. 1997). There are various OCD-related disorders, including Tourette syndrome (TS), grooming disorders (e.g., skin-picking, trichotillomania), and autism spectrum disorders (ASD) that share considerable overlapping features with OCD (Browne et al. 2014). Although the neurobiological basis of OCD still remains obscure, neuroimaging studies in patients with OCD and OCD-related disorders have consistently identified hyperactivity in orbitofrontal cortex and striatum (Cerliani et al. 2015; Hou et al. 2014; Jung et al. 2017; Neuner et al. 2014). However, the cellular and synaptic abnormalities underlying this hyperactivity are unclear. The most prominent theory regarding the underlying mechanisms of OCD and OCD-related disorders is an increased excitation to inhibition (E/I) ratio due to increased glutamatergic excitation or reduced GABAergic inhibition (Albin and Mink 2006; Rubenstein and Merzenich 2003; Wu et al. 2012). A proper E/I ratio is achieved by factors expressed in neuron and glia. In astrocytes, both the glutamate transporter GLT1 and GABA transporter GAT-3 are critical for regulating the E/I balance (Aida et al. 2015; Aizawa et al. 2020; Boddum et al. 2016; Cui et al. 2014; Kersanté et al. 2013; Kiryk et al. 2008; Matos et al. 2018; Scimemi 2014; Sugimoto et al. 2018; Sugiyama et al. 2017; Tanaka et al. 1997; Zhao et al. 2018). Although astrocyte dysfunction has not been directly explored in OCD patients, several animal studies have found that astrocytes are involved in the pathophysiology of OCD. In this chapter, I highlight recent studies in which astrocyte dysfunction contributed to E/I imbalance, leading to pathological repetitive behaviors shared between patients with OCD, TS, and ASD.
Collapse
Affiliation(s)
- Kohichi Tanaka
- Tokyo Medical and Dental University, Department of Molecular Neuroscience, Medical Research Institute, Tokyo, Japan.
| |
Collapse
|
|
48
|
Li X, Zhong H, Wang Z, Xiao R, Antonson P, Liu T, Wu C, Zou J, Wang L, Nalvarte I, Xu H, Warner M, Gustafsson JA, Fan X. Loss of liver X receptor β in astrocytes leads to anxiety-like behaviors via regulating synaptic transmission in the medial prefrontal cortex in mice. Mol Psychiatry 2021; 26:6380-6393. [PMID: 33963286 DOI: 10.1038/s41380-021-01139-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 04/08/2021] [Accepted: 04/19/2021] [Indexed: 02/03/2023]
Abstract
Astrocytes are integral components of synaptic transmission, and their dysfunction leads to neuropsychiatric disorders such as anxiety and depression. Liver X receptor β (LXRβ) is expressed in astrocytes, and LXRβ global knockout mice shows impaired synaptic formation. In order to define the role of LXRβ in astrocytes, we used a conditional Cre-loxP system to specifically remove LXRβ from astrocytes. We found that this deletion caused anxiety-like but not depressive-like behaviors in adult male mice. This behavioral phenotype could be completely reproduced by selective deletion of LXRβ in astrocytes in the medial prefrontal cortex (mPFC). Pyramidal neurons in layer V of mPFC are involved in mood behaviors. We found that there was an increased spontaneous excitatory synaptic transmission in layer V pyramidal neurons of the mPFC of these mice. This was concurrent with increased dendritic complexity, despite normal appearance and number of dendritic spines. In addition, gene ontology analysis of RNA sequencing revealed that deletion of astrocytic LXRβ led to the enrichment of the process of synaptic transmission in mPFC. Finally, we also confirmed that renormalized excitatory synaptic transmission in layer V pyramidal neurons alleviated the anxiety in mice with astrocytic LXRβ deletion in mPFC. Together, our findings reveal that astrocytic LXRβ in mPFC is critical in the regulation of synaptic transmission, and this provides a potential new target for treatment of anxiety-like behavior.
Collapse
Affiliation(s)
- Xin Li
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Hongyu Zhong
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Zhongke Wang
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Rui Xiao
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Per Antonson
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Tianyao Liu
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Chuan Wu
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Jiao Zou
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Lian Wang
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Ivan Nalvarte
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Margaret Warner
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Jan-Ake Gustafsson
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden. .,Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
| | - Xiaotang Fan
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China.
| |
Collapse
|
|
49
|
Gzielo K, Nikiforuk A. Astroglia in Autism Spectrum Disorder. Int J Mol Sci 2021; 22:11544. [PMID: 34768975 PMCID: PMC8583956 DOI: 10.3390/ijms222111544] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/13/2021] [Accepted: 10/21/2021] [Indexed: 01/12/2023] Open
Abstract
Autism spectrum disorder (ASD) is an umbrella term encompassing several neurodevelopmental disorders such as Asperger syndrome or autism. It is characterised by the occurrence of distinct deficits in social behaviour and communication and repetitive patterns of behaviour. The symptoms may be of different intensity and may vary in types. Risk factors for ASD include disturbed brain homeostasis, genetic predispositions, or inflammation during the prenatal period caused by viruses or bacteria. The number of diagnosed cases is growing, but the main cause and mechanism leading to ASD is still uncertain. Recent findings from animal models and human cases highlight the contribution of glia to the ASD pathophysiology. It is known that glia cells are not only "gluing" neurons together but are key players participating in different processes crucial for proper brain functioning, including neurogenesis, synaptogenesis, inflammation, myelination, proper glutamate processing and many others. Despite the prerequisites for the involvement of glia in the processes related to the onset of autism, there are far too little data regarding the engagement of these cells in the development of ASD.
Collapse
Affiliation(s)
- Kinga Gzielo
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Behavioral Neuroscience and Drug Development, 12 Smętna Street, 31-343 Kraków, Poland;
| | | |
Collapse
|
|
50
|
Della Vecchia S, Marchese M, Santorelli FM, Sicca F. Kir4.1 Dysfunction in the Pathophysiology of Depression: A Systematic Review. Cells 2021; 10:2628. [PMID: 34685608 PMCID: PMC8534194 DOI: 10.3390/cells10102628] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 09/28/2021] [Accepted: 09/28/2021] [Indexed: 12/17/2022] Open
Abstract
A serotonergic dysfunction has been largely postulated as the main cause of depression, mainly due to its effective response to drugs that increase the serotonergic tone, still currently the first therapeutic line in this mood disorder. However, other dysfunctional pathomechanisms are likely involved in the disorder, and this may in part explain why some individuals with depression are resistant to serotonergic therapies. Among these, emerging evidence suggests a role for the astrocytic inward rectifier potassium channel 4.1 (Kir4.1) as an important modulator of neuronal excitability and glutamate metabolism. To discuss the relationship between Kir4.1 dysfunction and depression, a systematic review was performed according to the PRISMA statement. Searches were conducted across PubMed, Scopus, and Web of Science by two independent reviewers. Twelve studies met the inclusion criteria, analyzing Kir4.1 relationships with depression, through in vitro, in vivo, and post-mortem investigations. Increasing, yet not conclusive, evidence suggests a potential pathogenic role for Kir4.1 upregulation in depression. However, the actual contribution in the diverse subtypes of the disorder and in the comorbid conditions, for example, the epilepsy-depression comorbidity, remain elusive. Further studies are needed to better define the clinical phenotype associated with Kir4.1 dysfunction in humans and the molecular mechanisms by which it contributes to depression and implications for future treatments.
Collapse
Affiliation(s)
- Stefania Della Vecchia
- Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Calambrone, 56128 Pisa, Italy;
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Maria Marchese
- Department of Molecular Medicine, IRCCS Stella Maris Foundation, Via dei Giacinti 2, 56128 Pisa, Italy;
| | - Filippo Maria Santorelli
- Department of Molecular Medicine, IRCCS Stella Maris Foundation, Via dei Giacinti 2, 56128 Pisa, Italy;
| | - Federico Sicca
- Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Calambrone, 56128 Pisa, Italy;
- Child Neuropsychiatric Unit, USL Centro Toscana, 59100 Prato, Italy
| |
Collapse
|