|
1
|
Borrego-Ruiz A, Borrego JJ. Involvement of virus infections and antiviral agents in schizophrenia. Psychol Med 2025; 55:e73. [PMID: 40059820 PMCID: PMC12055031 DOI: 10.1017/s0033291725000467] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 02/06/2025] [Accepted: 02/12/2025] [Indexed: 05/08/2025]
Abstract
BACKGROUND Schizophrenia is a chronic and complex mental disorder resulting from interactions between cumulative and synergistic genetic and environmental factors. Viral infection during the prenatal stage constitutes one of the most relevant risk factors for the development of schizophrenia later in adulthood. METHODS A narrative review was conducted to explore the link between viral infections and schizophrenia, as well as the neuropsychiatric effects of antiviral drugs, particularly in the context of this specific mental condition. Literature searches were performed using the PubMed, Scopus, and Web of Science databases. RESULTS Several viral infections, such as herpesviruses, influenza virus, Borna disease virus, and coronaviruses, can directly or indirectly disrupt normal fetal brain development by modifying gene expression in the maternal immune system, thereby contributing to the pathophysiological symptoms of schizophrenia. In addition, neuropsychiatric effects caused by antiviral drugs are frequent and represent significant adverse outcomes for viral treatment. CONCLUSIONS Epidemiological evidence suggests a potential relationship between viruses and schizophrenia. Increases in inflammatory cytokine levels and changes in the expression of key genes observed in several viral infections may constitute potential links between these viral infections and schizophrenia. Furthermore, antivirals may affect the central nervous system, although for most drugs, their mechanisms of action are still unclear, and a strong relationship between antivirals and schizophrenia has not yet been established.
Collapse
Affiliation(s)
- Alejandro Borrego-Ruiz
- Departamento de Psicología Social y de las Organizaciones, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Juan J. Borrego
- Departamento de Microbiología, Universidad de Málaga, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA, Plataforma BIONAND, Málaga, Spain
| |
Collapse
|
|
2
|
Al-Kuraishy HM, Al-Gareeb AI, Alexiou A, Mukerjee N, Al-Hamash SMJ, Al-Maiahy TJ, Batiha GES. 5-HT/CGRP pathway and Sumatriptan role in Covid-19. Biotechnol Genet Eng Rev 2024; 40:3148-3173. [PMID: 36042570 DOI: 10.1080/02648725.2022.2108996] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/21/2022] [Indexed: 12/27/2022]
Abstract
Coronavirus disease 2019 (Covid-19) is a pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In Covid-19, there is uncontrolled activation of immune cells with a massive release of pro-inflammatory cytokines and the development of cytokine storm. These inflammatory changes induce impairment of different organ functions, including the central nervous system (CNS), leading to acute brain injury and substantial changes in the neurotransmitters, including serotonin (5-HT) and calcitonin gene-related peptide (CGRP), which have immunomodulatory properties through modulation of central and peripheral immune responses. In Covid-19, 5-HT neurotransmitters and CGRP could contribute to abnormal and atypical vascular reactivity. Sumatriptan is a pre-synaptic 5-HT (5-HT1D and 5-HT1B) agonist and inhibits the release of CGRP. Both 5-HT and CGRP seem to be augmented in Covid-19 due to underlying activation of inflammatory signaling pathways and hyperinflammation. In virtue of its anti-inflammatory and antioxidant properties with inhibition release of 5-HT and CGRP, Sumatriptan may reduce Covid-19 hyperinflammation. Therefore, Sumatriptan might be a novel potential therapeutic strategy in managing Covid-19. In conclusion, Sumatriptan could be an effective therapeutic strategy in managing Covid-19 through modulation of 5-HT neurotransmitters and inhibiting CGRP.
Collapse
Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, AL-Mustansiriyah University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, AL-Mustansiriyah University, Baghdad, Iraq
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW, Australia
- AFNP Med, Wien, Austria
| | - Nobendu Mukerjee
- Department of Microbiology, Ramakrishna Mission Vivekananda Centenary College, Kolkata, India
- Department of Health Sciences, Novel Global Community Educational Foundation, Hebersham, NSW, Australia
| | | | - Thabat J Al-Maiahy
- Department of Gynecology and Obstetrics, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
| |
Collapse
|
|
3
|
Park ES, Shin CY, Jeon SJ, Ham BJ. Is There such a Thing as Post-Viral Depression?: Implications for Precision Medicine. Biomol Ther (Seoul) 2024; 32:659-684. [PMID: 39428555 PMCID: PMC11535299 DOI: 10.4062/biomolther.2024.170] [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: 09/10/2024] [Revised: 10/06/2024] [Accepted: 10/07/2024] [Indexed: 10/22/2024] Open
Abstract
Viral infections are increasingly recognized as triggers for depressive disorders, particularly following the SARS-CoV-2 pandemic and the rise of long COVID. Viruses such as Herpes Simplex Virus (HSV), Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), and Human Immunodeficiency Virus (HIV) are linked to depression through complex neurobiological mechanisms. These include immune system dysregulation, chronic inflammation, and neurotransmitter imbalances that affect brain function and mood regulation. Viral activation of the immune system leads to the release of pro-inflammatory cytokines, resulting in neuroinflammation and associated depressive symptoms. Furthermore, specific viruses can disrupt neurotransmitter systems, including serotonin, dopamine, and glutamate, all of which are essential for mood stabilization. The unique interactions of different viruses with these systems underscore the need for virus-specific therapeutic approaches. Current broad-spectrum treatments often overlook the precise neurobiological pathways involved in post-viral depression, reducing their efficacy. This review emphasizes the need to understand these virus-specific interactions to create tailored interventions that directly address the neurobiological effects induced by each type of virus. These interventions may include immunomodulatory treatments that target persistent inflammation, antiviral therapies to reduce the viral load, or neuroprotective strategies that restore neurotransmitter balance. Precision medicine offers promising avenues for the effective management of virus-induced depression, providing patient-specific approaches that address the specific biological mechanisms involved. By focusing on the development of these targeted treatments, this review aims to pave the way for a new era in psychiatric care that fully addresses the root causes of depression induced by viral infections.
Collapse
Affiliation(s)
- Eun-Sook Park
- Institute of Biomedical Science and Technology, School of Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Chan Young Shin
- School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul 05029, Republic of Korea
- Department of Pharmacology and Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul 05029, Republic of Korea
- Institute of Biomedical Sciences & Technology, Konkuk University, Seoul 05029, Republic of Korea
| | - Se Jin Jeon
- Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Byung-Joo Ham
- Department of Psychiatry, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
| |
Collapse
|
|
4
|
Luo C, Yang Y, Jiang C, Lv A, Zuo W, Ye Y, Ke J. Influenza and the gut microbiota: A hidden therapeutic link. Heliyon 2024; 10:e37661. [PMID: 39315196 PMCID: PMC11417228 DOI: 10.1016/j.heliyon.2024.e37661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 07/31/2024] [Accepted: 09/07/2024] [Indexed: 09/25/2024] Open
Abstract
Background The extensive community of gut microbiota significantly influences various biological functions throughout the body, making its characterization a focal point in biomedicine research. Over the past few decades, studies have revealed a potential link between specific gut bacteria, their associated metabolic pathways, and influenza. Bacterial metabolites can communicate directly or indirectly with organs beyond the gut via the intestinal barrier, thereby impacting the physiological functions of the host. As the microbiota increasingly emerges as a 'gut signature' in influenza, gaining a deeper understanding of its role may offer new insights into its pathophysiological relevance and open avenues for novel therapeutic targets. In this Review, we explore the differences in gut microbiota between healthy individuals and those with influenza, the relationship between gut microbiota metabolites and influenza, and potential strategies for preventing and treating influenza through the regulation of gut microbiota and its metabolites, including fecal microbiota transplantation and microecological preparations. Methods We utilized PubMed and Web of Science as our search databases, employing keywords such as "influenza," "gut microbiota," "traditional Chinese medicine," "metabolites," "prebiotics," "probiotics," and "machine learning" to retrieve studies examining the potential therapeutic connections between the modulation of gut microbiota and its metabolites in the treatment of influenza. The search encompassed literature from the inception of the databases up to December 2023. Results Fecal microbiota transplantation (FMT), microbial preparations (probiotics and prebiotics), and traditional Chinese medicine have unique advantages in regulating intestinal microbiota and its metabolites to improve influenza outcomes. The primary mechanism involves increasing beneficial intestinal bacteria such as Bacteroidetes and Bifidobacterium while reducing harmful bacteria such as Proteobacteria. These interventions act directly or indirectly on metabolites such as short-chain fatty acids (SCFAs), amino acids (AAs), bile acids, and monoamines to alleviate lung inflammation, reduce viral load, and exert anti-influenza virus effects. Conclusion The gut microbiota and its metabolites have direct or indirect therapeutic effects on influenza, presenting broad research potential for providing new directions in influenza research and offering references for clinical prevention and treatment. Future research should focus on identifying key strains, specific metabolites, and immune regulation mechanisms within the gut microbiota to accurately target microbiota interventions and prevent respiratory viral infections such as influenza.
Collapse
Affiliation(s)
- Cheng Luo
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610032, China
| | - Yi Yang
- Hubei Provincial Hospital of Traditional Chinese Medicine, Hubei Academy of Traditional Chinese Medicine, Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, 430074, China
| | - Cheng Jiang
- Hubei Provincial Hospital of Traditional Chinese Medicine, Hubei Academy of Traditional Chinese Medicine, Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, 430074, China
| | - Anqi Lv
- College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, 430061, China
| | - Wanzhao Zuo
- College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, 430061, China
| | - Yuanhang Ye
- College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, 430061, China
| | - Jia Ke
- Hubei Provincial Hospital of Traditional Chinese Medicine, Hubei Academy of Traditional Chinese Medicine, Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, 430074, China
| |
Collapse
|
|
5
|
Chou S, Wu R, Li M. Long-term impacts of prenatal maternal immune activation and postnatal maternal separation on maternal behavior in adult female rats: Relevance to postpartum mental disorders. Behav Brain Res 2024; 461:114831. [PMID: 38142861 PMCID: PMC10872411 DOI: 10.1016/j.bbr.2023.114831] [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: 11/12/2023] [Revised: 12/19/2023] [Accepted: 12/19/2023] [Indexed: 12/26/2023]
Abstract
Early life adversities are known to exert long-term negative impacts on psychological and brain functions in adulthood. The present work examined how a prenatal brain insult and a postnatal stressor independently or interactively influence the quality of maternal care of postpartum female rats and their cognitive and emotional functions, as a way to identify the behavioral dysfunctions underlying childhood trauma-induced postpartum mental disorders (as indexed by impaired maternal care). Sprague-Dawley female offspring born from mother rats exposed to polyinosinic:polycytidylic acid (PolyI:C, 4.0-6.0 mg/kg) intended to cause gestational maternal immune activation (MIA) or saline were subjected to a repeated maternal separation stress (RMS, 3 h/day) or no separation for 9 days in the first two weeks of life (a 2 × 2 design). When these offspring became mothers, their attentional filtering ability (as measured in the prepulse inhibition of acoustic startle reflex test), positive hedonic response (as measured in the sucrose preference test), and negative emotional response (as measured in the startle reflex and fear-potentiated startle test) were examined, along with their home-cage maternal behavior. Virgin littermates served as controls in all the behavioral tests except in maternal behavior. Results showed that mother rats who experienced RMS displayed impaired nest building and crouching/nursing activities. RMS also interacted with MIA to alter pup retrieval latency and startle reactivity, such that MIA-RMS dams demonstrated significantly slower pup retrieval latency and higher startle magnitude compared to either RMS-only and MIA-only mothers. MIA also disrupted attentional filtering ability, with significantly lower prepulse inhibition. However, neither prenatal MIA nor postnatal RMS impaired sucrose preference or the acquisition of fear-potentiated startle. These results indicate that prenatal stress and postnatal adversity could impair maternal behavior individually, and interact with each other, causing impairments in attention, emotion and maternal motivation.
Collapse
Affiliation(s)
- Shinnyi Chou
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ruiyong Wu
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China
| | - Ming Li
- Department of Psychology, Nanjing University, Nanjing, China.
| |
Collapse
|
|
6
|
DelaCuesta-Barrutia J, Martínez-Peula O, Rivero G, Santas-Martín JA, Munarriz-Cuezva E, Brocos-Mosquera I, Miranda-Azpiazu P, Diez-Alarcia R, Morentin B, Honer WG, Callado LF, Erdozain AM, Ramos-Miguel A. Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects. Transl Psychiatry 2024; 14:113. [PMID: 38396013 PMCID: PMC10891050 DOI: 10.1038/s41398-024-02832-z] [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: 09/14/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu2R and mGlu3R) in brains of schizophrenia patients may explain the limited efficacy of mGlu2/3R ligands in clinical trials. Studies evaluating mGlu2/3R levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected. Toxicological analyses identified cases who were (AP+) or were not (AP-) receiving antipsychotic treatment near the time of death. Protein and mRNA levels of mGlu2R and mGlu3R, as well as GRM2 and GRM3 promoter-attached histone posttranslational modifications, were quantified. Experimental animal models were used to compare with data obtained in human tissues. Compared to matched controls, schizophrenia cortical samples had lower mGlu2R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu3R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D2 and serotonin 5HT2A receptors correlated with higher density of mGlu3R, but not mGlu2R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu2R, but not mGlu3R regulation observed in schizophrenia brains. mGlu2R and mGlu3R mRNA levels, and the epigenetic control mechanisms did not parallel the alterations at the protein level, and in some groups correlated inversely. Insufficient cortical availability of mGlu2R and mGlu3R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu3R, but not mGlu2R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu3R expression are activated to counterbalance mGluR loss of function is described.
Collapse
Affiliation(s)
| | | | - Guadalupe Rivero
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Leioa, Spain
| | - Jon A Santas-Martín
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Eva Munarriz-Cuezva
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Leioa, Spain
| | - Iria Brocos-Mosquera
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain
| | | | - Rebeca Diez-Alarcia
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Leioa, Spain
| | - Benito Morentin
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Basque Institute of Legal Medicine, Bilbao, Spain
| | - William G Honer
- Department Psychiatry, University of British Columbia, Vancouver, BC, Canada
| | - Luis F Callado
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Leioa, Spain
| | - Amaia M Erdozain
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Leioa, Spain
| | - Alfredo Ramos-Miguel
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain.
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Leioa, Spain.
| |
Collapse
|
|
7
|
Lotfi N, Rezaei N, Rastgoo E, Khodadoustan Shahraki B, Zahedi G, Jafarinia M. Schizophrenia Etiological Factors and Their Correlation with the Imbalance of the Immune System: An Update. Galen Med J 2023; 12:e3109. [PMID: 39553412 PMCID: PMC11568428 DOI: 10.31661/gmj.v12i.3109] [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: 07/01/2023] [Revised: 07/16/2023] [Accepted: 07/24/2023] [Indexed: 11/19/2024] Open
Abstract
Schizophrenia (SZ) is a severe psychiatric disorder associated with a dysregulation of the immune system. Immune-related genes and environmental factors including stress, food, infections, and microbiota, alter the immune system's homeostasis and play a role in SZ pathogenesis. The most distinctive feature in the pathophysiology of the disease is a shift in the T helper 1(Th1)/Th2 balance toward Th2 dominance in the immune system. Also, microglial and Th17 cell activation cause inflammatory responses in the central nervous system (CNS). Antibodies play a role in the pathophysiology of SZ and give more evidence of a link between humoral immune reactivity and the disease. Accordingly, an imbalance in cytokine activities and neuroinfl ammation has been considered the main contributor to the pathogenesis of the SZ. Overall, the deregulation of the immune system caused by genetic, environmental, and neurochemical effects may all play a role in the etiology of SZ. This review summarized the etiological factors for SZ and discussed the role of immune responses and their interaction with genetic and environmental factors in SZ pathogenesis.
Collapse
Affiliation(s)
- Noushin Lotfi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nahid Rezaei
- Department of Immunology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Elham Rastgoo
- Department of Radiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Ghazaleh Zahedi
- Department of General Psychology, Iran University of Medical Sciences, Thran, Iran
| | - Morteza Jafarinia
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
|
8
|
Bugaeva P, Arkusha I, Bikaev R, Kamenskiy I, Pokrovskaya A, El-Taravi Y, Caso V, Avedisova A, Chu DK, Genuneit J, Torbahn G, Nicholson TR, Baimukhambetova D, Mursalova A, Kolotilina A, Gadetskaya S, Kondrikova E, Zinchuk M, Akzhigitov R, Boyle RJ, Guekht A, Munblit D. Association of breastfeeding with mental disorders in mother and child: a systematic review and meta-analysis. BMC Med 2023; 21:393. [PMID: 37840122 PMCID: PMC10577970 DOI: 10.1186/s12916-023-03071-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 09/06/2023] [Indexed: 10/17/2023] Open
Abstract
BACKGROUND Breastfeeding has long been associated with numerous benefits for both mothers and infants. While some observational studies have explored the relationship between breastfeeding and mental health outcomes in mothers and children, a systematic review of the available evidence is lacking. The purpose of this study is to systematically evaluate the association between breastfeeding and mental health disorders in mothers and children. METHODS We systematically searched MEDLINE and EMBASE from inception to June 2, 2023. The inclusion criteria consisted of all studies evaluating links between breastfeeding and development of mental health disorders in children and mothers. Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) while grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of evidence. A random-effects meta-analysis was used if possible, to estimate the odds ratio for the association between breastfeeding and mental health outcomes. The Mantel-Haenszel method was utilised for pooling ORs across studies. Study heterogeneity was assessed using the I2 statistic. RESULTS Our review identified twenty-one original study. Of these, 18 focused on the association between breastfeeding and child health, assessing depressive disorders, schizophrenia, anxiety disorders, eating disorders and borderline personality disorder. Three studies evaluated the associations between breastfeeding and maternal mental health disorders. Three studies looking at outcomes in children showed no significant association between breastfeeding and occurrence of schizophrenia later in life (OR 0.98; 95% CI 0.57-1.71; I2 = 29%). For depressive disorders (5 studies) and anxiety disorders (3 studies), we found conflicting evidence with some studies showing a small protective effect while others found no effect. The GRADE certainty for all these findings was very low due to multiple limitations. Three studies looking at association between breastfeeding and maternal mental health, were too heterogeneous to draw any firm conclusions. CONCLUSIONS We found limited evidence to support a protective association between breastfeeding and the development of mental health disorders in children later in life. The data regarding the association between breastfeeding and maternal mental health beyond the postnatal period is also limited. The methodological limitations of the published literature prevent definitive conclusions, and further research is needed to better understand the relationship between breastfeeding and mental health in mothers and children.
Collapse
Affiliation(s)
- Polina Bugaeva
- Charité - Universitätsmedizin Berlin, Einstein Center for Neurosciences, Berlin, Germany
| | - Inna Arkusha
- V. Serbsky Federal Medical Research Center for Psychiatry and Narcology of the Ministry of Health of the Russian Federation, Moscow, Russia
- Moscow Research and Clinical Centre for Neuropsychiatry, Moscow, Russia
| | - Rinat Bikaev
- Moscow Research and Clinical Centre for Neuropsychiatry, Moscow, Russia
| | - Igor Kamenskiy
- Moscow City Clinical Hospital After V.M. Buyanov, Moscow, Russia
| | - Aleksandra Pokrovskaya
- Department of Brain Sciences, Faculty of Medicine, Dementia Research Institute UK, Imperial College London, London, UK
| | | | - Valeria Caso
- Stroke Unit, Santa Maria Della Misericordia Hospital, University of Perugia, Perugia, Italy
| | - Alla Avedisova
- V. Serbsky Federal Medical Research Center for Psychiatry and Narcology of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Derek K Chu
- Division of Clinical Immunology & Allergy, Department of Medicine, and Department of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Canada
| | - Jon Genuneit
- Department of Pediatrics, Pediatric Epidemiology, Medical Faculty, Leipzig University, Leipzig, Germany
- German Center for Child and Youth Health, Leipzig, Germany
| | - Gabriel Torbahn
- Department of Pediatrics, Paracelsus Medical University, Klinikum Nürnberg, Universitätsklinik Der Paracelsus Medizinischen Privatuniversität Nürnberg, Nuremberg, Germany
- Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Timothy R Nicholson
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Dina Baimukhambetova
- Department of Paediatrics and Paediatric Infectious Diseases, Institute of Child's Health, I.M. Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia
| | - Aigun Mursalova
- Department of Paediatrics and Paediatric Infectious Diseases, Institute of Child's Health, I.M. Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia
| | - Anastasia Kolotilina
- Department of Paediatrics and Paediatric Infectious Diseases, Institute of Child's Health, I.M. Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia
| | - Svetlana Gadetskaya
- Department of Paediatrics and Paediatric Infectious Diseases, Institute of Child's Health, I.M. Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia
| | - Elena Kondrikova
- Department of Paediatrics and Paediatric Infectious Diseases, Institute of Child's Health, I.M. Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia
| | - Mikhail Zinchuk
- Moscow Research and Clinical Centre for Neuropsychiatry, Moscow, Russia
| | - Renat Akzhigitov
- Moscow Research and Clinical Centre for Neuropsychiatry, Moscow, Russia
| | - Robert J Boyle
- National Heart and Lung Institute, Imperial College London, London, UK.
| | - Alla Guekht
- Moscow Research and Clinical Centre for Neuropsychiatry, Moscow, Russia
| | - Daniel Munblit
- National Heart and Lung Institute, Imperial College London, London, UK.
- Care for Long Term Conditions Division, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, London, UK.
- I.M. Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia.
- Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, United Kingdom.
| |
Collapse
|
|
9
|
Al-Beltagi M, Saeed NK, Elbeltagi R, Bediwy AS, Aftab SAS, Alhawamdeh R. Viruses and autism: A Bi-mutual cause and effect. World J Virol 2023; 12:172-192. [PMID: 37396705 PMCID: PMC10311578 DOI: 10.5501/wjv.v12.i3.172] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/16/2023] [Accepted: 04/18/2023] [Indexed: 06/21/2023] Open
Abstract
Autism spectrum disorder (ASD) is a group of heterogeneous, multi-factorial, neurodevelopmental disorders resulting from genetic and environmental factors interplay. Infection is a significant trigger of autism, especially during the critical developmental period. There is a strong interplay between the viral infection as a trigger and a result of ASD. We aim to highlight the mutual relationship between autism and viruses. We performed a thorough literature review and included 158 research in this review. Most of the literature agreed on the possible effects of the viral infection during the critical period of development on the risk of developing autism, especially for specific viral infections such as Rubella, Cytomegalovirus, Herpes Simplex virus, Varicella Zoster Virus, Influenza virus, Zika virus, and severe acute respiratory syndrome coronavirus 2. Viral infection directly infects the brain, triggers immune activation, induces epigenetic changes, and raises the risks of having a child with autism. At the same time, there is some evidence of increased risk of infection, including viral infections in children with autism, due to lots of factors. There is an increased risk of developing autism with a specific viral infection during the early developmental period and an increased risk of viral infections in children with autism. In addition, children with autism are at increased risk of infection, including viruses. Every effort should be made to prevent maternal and early-life infections and reduce the risk of autism. Immune modulation of children with autism should be considered to reduce the risk of infection.
Collapse
Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta 31511, Alghrabia, Egypt
- Department of Pediatrics, University Medical Center, King Abdulla Medical City, Dr. Sulaiman Al Habib Medical Group, Manama 26671, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Pathology Department, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Bahrain
- Microbiology Section, Pathology Department, Irish Royal College of Surgeon, Busaiteen 15503, Muharraq, Bahrain
| | - Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland - Bahrain, Busiateen 15503, Muharraq, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonolgy, Faculty of Medicine, Tanta University, Tanta 31527, Alghrabia, Egypt
- Department of Chest Disease, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Dr. Sulaiman Al Habib Medical Group, Manama 26671, Bahrain
| | - Syed A Saboor Aftab
- Endocrinology and DM, William Harvey Hospital (Paula Carr Centre), Ashford TN24 0LZ, Kent, United Kingdom
| | - Rawan Alhawamdeh
- Pediatrics Research and Development, Genomics Creativity and Play Center, Manama 0000, Bahrain
| |
Collapse
|
|
10
|
Matrisciano F. Epigenetic regulation of metabotropic glutamate 2/3 receptors: Potential role for ultra-resistant schizophrenia? Pharmacol Biochem Behav 2023:173589. [PMID: 37348609 DOI: 10.1016/j.pbb.2023.173589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/05/2023] [Accepted: 06/15/2023] [Indexed: 06/24/2023]
Abstract
Schizophrenia is a severe and debilitating psychiatric disorder characterized by early cognitive deficits, emotional and behavioral abnormalities resulted by a dysfunctional gene x environment interaction. Genetic and epigenetic abnormalities in cortical parvalbumin-positive GABAergic interneurons lead to alterations in glutamate-mediated excitatory neurotransmission, synaptic plasticity, and neuronal development. Epigenetic alterations during pregnancy or early phases of postnatal life are associated with schizophrenia vulnerability as well as inflammatory processes which are at the basis of brain pathology. An epigenetic animal model of schizophrenia showed specific changes in promoter DNA methylation activity of genes related to schizophrenia such as reelin, BDNF and GAD67, and altered expression and function of mGlu2/3 receptors in the frontal cortex. Although antipsychotic medications represent the main treatment for schizophrenia and generally show an optimal efficacy profile for positive symptoms and relatively poor efficacy for negative or cognitive symptoms, a considerable percentage of individuals show poor response, do not achieve a complete remission, and approximately 30 % of patients show treatment-resistance. Here, we explore the potential role of epigenetic abnormalities linked to metabotropic glutamate 2/3 receptors changes in expression and function as key molecular factors underlying the difference in response to antipsychotics.
Collapse
Affiliation(s)
- Francesco Matrisciano
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago (UIC), Chicago, IL, USA.
| |
Collapse
|
|
11
|
Paumgartten FJR, De Grava Kempinas W, Shiota K. Viral infections, vaccines and antiviral drugs in pregnancy and the development of the conceptus. Reprod Toxicol 2023; 115:36-39. [PMID: 36403853 DOI: 10.1016/j.reprotox.2022.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
| | - Wilma De Grava Kempinas
- Laboratory of Reproductive and Developmental Biology and Toxicology, Department of structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, SP, Brazil
| | | |
Collapse
|
|
12
|
Hall MB, Willis DE, Rodriguez EL, Schwarz JM. Maternal immune activation as an epidemiological risk factor for neurodevelopmental disorders: Considerations of timing, severity, individual differences, and sex in human and rodent studies. Front Neurosci 2023; 17:1135559. [PMID: 37123361 PMCID: PMC10133487 DOI: 10.3389/fnins.2023.1135559] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 03/13/2023] [Indexed: 05/02/2023] Open
Abstract
Epidemiological evidence suggests that one's risk of being diagnosed with a neurodevelopmental disorder (NDD)-such as autism, ADHD, or schizophrenia-increases significantly if their mother had a viral or bacterial infection during the first or second trimester of pregnancy. Despite this well-known data, little is known about how developing neural systems are perturbed by events such as early-life immune activation. One theory is that the maternal immune response disrupts neural processes important for typical fetal and postnatal development, which can subsequently result in specific and overlapping behavioral phenotypes in offspring, characteristic of NDDs. As such, rodent models of maternal immune activation (MIA) have been useful in elucidating neural mechanisms that may become dysregulated by MIA. This review will start with an up-to-date and in-depth, critical summary of epidemiological data in humans, examining the association between different types of MIA and NDD outcomes in offspring. Thereafter, we will summarize common rodent models of MIA and discuss their relevance to the human epidemiological data. Finally, we will highlight other factors that may interact with or impact MIA and its associated risk for NDDs, and emphasize the importance for researchers to consider these when designing future human and rodent studies. These points to consider include: the sex of the offspring, the developmental timing of the immune challenge, and other factors that may contribute to individual variability in neural and behavioral responses to MIA, such as genetics, parental age, the gut microbiome, prenatal stress, and placental buffering.
Collapse
|
|
13
|
Saunders JM, Muguruza C, Sierra S, Moreno JL, Callado LF, Meana JJ, Beardsley PM, González-Maeso J. Glucocorticoid receptor dysregulation underlies 5-HT 2AR-dependent synaptic and behavioral deficits in a mouse neurodevelopmental disorder model. J Biol Chem 2022; 298:102481. [PMID: 36100039 DOI: 10.1016/j.jbc.2022.102481] [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: 05/27/2022] [Revised: 09/01/2022] [Accepted: 09/03/2022] [Indexed: 11/25/2022] Open
Abstract
Prenatal environmental insults increase the risk of neurodevelopmental psychiatric conditions in the offspring. Structural modifications of dendritic spines are central to brain development and plasticity. Using maternal immune activation (MIA) as a rodent model of prenatal environmental insult, previous results have reported dendritic structural deficits in the frontal cortex. However, very little is known about the molecular mechanism underlying MIA-induced synaptic structural alterations in the offspring. Using prenatal (E12.5) injection with poly-(I:C) as a mouse MIA model, we show here that upregulation of the serotonin 5-HT2A receptor (5-HT2AR) is at least in part responsible for some of the effects of prenatal insults on frontal cortex dendritic spine structure and sensorimotor gating processes. Mechanistically, we report that this upregulation of frontal cortex 5-HT2AR expression is associated with MIA-induced reduction of nuclear translocation of the glucocorticoid receptor (GR) and, consequently, a decrease in the enrichment of GR at the 5-HT2AR promoter. The translational significance of these preclinical findings is supported by data in postmortem human brain samples suggesting dysregulation of GR translocation in frontal cortex of schizophrenia subjects. We also found that repeated corticosterone administration augmented frontal cortex 5-HT2AR expression and reduced GR binding to the 5-HT2AR promoter. However, virally (AAV)-mediated augmentation of GR function reduced frontal cortex 5-HT2AR expression and improved sensorimotor gating processes via 5-HT2AR. Together, these data support a negative regulatory relationship between GR signaling and 5-HT2AR expression in the mouse frontal cortex that may carry implications for the pathophysiology underlying 5-HT2AR dysregulation in neurodevelopmental psychiatric disorders.
Collapse
Affiliation(s)
- Justin M Saunders
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
| | - Carolina Muguruza
- Department of Pharmacology, University of the Basque Country UPV/EHU, CIBERSAM, Biocruces Bizkaia Health Research Institute, E-48940 Leioa, Bizkaia, Spain
| | - Salvador Sierra
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
| | - José L Moreno
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
| | - Luis F Callado
- Department of Pharmacology, University of the Basque Country UPV/EHU, CIBERSAM, Biocruces Bizkaia Health Research Institute, E-48940 Leioa, Bizkaia, Spain
| | - J Javier Meana
- Department of Pharmacology, University of the Basque Country UPV/EHU, CIBERSAM, Biocruces Bizkaia Health Research Institute, E-48940 Leioa, Bizkaia, Spain
| | - Patrick M Beardsley
- Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University School of Pharmacy, Richmond, VA 23298, USA
| | - Javier González-Maeso
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
| |
Collapse
|
|
14
|
Glatfelter GC, Chojnacki MR, McGriff SA, Wang T, Baumann MH. Automated Computer Software Assessment of 5-Hydroxytryptamine 2A Receptor-Mediated Head Twitch Responses from Video Recordings of Mice. ACS Pharmacol Transl Sci 2022; 5:321-330. [PMID: 35592434 PMCID: PMC9112414 DOI: 10.1021/acsptsci.1c00237] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Indexed: 02/08/2023]
Abstract
Psychedelics are a class of drugs that produce unique subjective effects via agonist actions at the 5-hydroxytryptamine 2A receptor (5-HT2A). The 5-HT2A-mediated head twitch response (HTR) in rodents is used as a reliable proxy for psychedelic drug activity in humans, but existing methods for measuring HTRs require surgery or time-consuming visual scoring. In the present work, we validated a simple noninvasive method for quantitating HTRs using computer-based analysis of experimental video recordings. Male C57BL/6J mice received injections of the 5-HT2 receptor agonist (±)2,5-dimethoxy-4-iodoamphetamine (DOI; 0.03-3 mg/kg, s.c.) and were placed into cylindrical arenas. High frame rate videos were recorded via cameras mounted above the arenas. Antagonist experiments, which entailed pretreatment with the 5-HT2A antagonist M100907 (0.01 or 0.1 mg/kg s.c.) prior to DOI (1 mg/kg s.c.), were also recorded. The experimental videos were analyzed for HTRs using a newly developed feature of a commercial software package and compared to visual scoring carried out by trained observers. As expected, DOI produced dose-related increases in HTRs, which were blocked by M100907. Computer scoring was positively correlated with visual scoring, and no statistical difference between the two methods was found. The software captured nearly all visually observed HTRs, false positives induced by other behaviors (e.g., grooming) were rare and easily identified, and results were improved by optimizing lighting conditions. Our findings demonstrate the utility of combining high frame rate video recordings with commercial software analyses to measure HTRs, validating an additional reliable method to study psychedelic-like drug activity in mice.
Collapse
Affiliation(s)
- Grant C. Glatfelter
- Designer
Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, United States
| | - Michael R. Chojnacki
- Designer
Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, United States
| | - Shelby A. McGriff
- Designer
Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, United States
| | - Tianpeng Wang
- Clever
Sys Inc., Reston, Virginia 20190, United
States
| | - Michael H. Baumann
- Designer
Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, United States
| |
Collapse
|
|
15
|
Andrade CA, Kalergis AM, Bohmwald K. Potential Neurocognitive Symptoms Due to Respiratory Syncytial Virus Infection. Pathogens 2021; 11:47. [PMID: 35055995 PMCID: PMC8780657 DOI: 10.3390/pathogens11010047] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/23/2021] [Accepted: 11/30/2021] [Indexed: 01/03/2023] Open
Abstract
Respiratory infections are among the major public health burdens, especially during winter. Along these lines, the human respiratory syncytial virus (hRSV) is the principal viral agent causing acute lower respiratory tract infections leading to hospitalization. The pulmonary manifestations due to hRSV infection are bronchiolitis and pneumonia, where the population most affected are infants and the elderly. However, recent evidence suggests that hRSV infection can impact the mother and fetus during pregnancy. Studies have indicated that hRSV can infect different cell types from the placenta and even cross the placenta barrier and infect the fetus. In addition, it is known that infections during the gestational period can lead to severe consequences for the development of the fetus due not only to a direct viral infection but also because of maternal immune activation (MIA). Furthermore, it has been described that the development of the central nervous system (CNS) of the fetus can be affected by the inflammatory environment of the uterus caused by viral infections. Increasing evidence supports the notion that hRSV could invade the CNS and infect nervous cells, such as microglia, neurons, and astrocytes, promoting neuroinflammation. Moreover, it has been described that the hRSV infection can provoke neurological manifestations, including cognitive impairment and behavioral alterations. Here, we will review the potential effect of hRSV in brain development and the potential long-term neurological sequelae.
Collapse
Affiliation(s)
- Catalina A. Andrade
- Department of Molecular and Microbiology, Faculty of Biological Science, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile;
| | - Alexis M. Kalergis
- Department of Molecular and Microbiology, Faculty of Biological Science, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile;
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile
| | - Karen Bohmwald
- Department of Molecular and Microbiology, Faculty of Biological Science, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile;
| |
Collapse
|
|
16
|
Zhou L, Bao L, Wang Y, Chen M, Zhang Y, Geng Z, Zhao R, Sun J, Bao Y, Shi Y, Yao R, Guo S, Cui X. An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication. Front Pharmacol 2021; 12:755796. [PMID: 34867371 PMCID: PMC8640456 DOI: 10.3389/fphar.2021.755796] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 10/19/2021] [Indexed: 11/13/2022] Open
Abstract
Geniposide, an iridoid glycoside purified from the fruit of Gardenia jasminoides J.Ellis, has been reported to possess pleiotropic activity against different diseases. In particular, geniposide possesses a variety of biological activities and exerts good therapeutic effects in the treatment of several strains of the influenza virus. However, the molecular mechanism for the therapeutic effect has not been well defined. This study aimed to investigate the mechanism of geniposide on influenza A virus (IAV). The potential targets and signaling pathways of geniposide in the IAV infection were predicted using network pharmacology analysis. According to the result of network pharmacology analysis, we validated the calcium signaling pathway induced by IAV and investigated the effect of geniposide extracted from Gardenia jasminoides J.Ellis on this pathway. The primary Gene Ontology (GO) biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways KEGG enrichment analysis indicated that geniposide has a multi-target and multi-pathway inhibitory effect against influenza, and one of the mechanisms involves calcium signaling pathway. In the current study, geniposide treatment greatly decreased the levels of RNA polymerase in HEK-293T cells infected with IAV. Knocking down CAMKII in IAV-infected HEK-293T cells enhanced virus RNA (vRNA) production. Geniposide treatment increased CAMKII expression after IAV infection. Meanwhile, the CREB and c-Fos expressions were inhibited by geniposide after IAV infection. The experimental validation data showed that the geniposide was able to alleviate extracellular Ca2+ influx, dramatically decreased neuraminidase activity, and suppressed IAV replication in vitro via regulating the calcium signaling pathway. These anti-IAV effects might be related to the disrupted interplay between IAV RNA polymerase and CAMKII and the regulation of the downstream calcium signaling pathway essential for IAV replication. Taken together, the findings reveal a new facet of the mechanism by which geniposide fights IAV in a way that depends on CAMKII replication.
Collapse
Affiliation(s)
- Lirun Zhou
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lei Bao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yaxin Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mengping Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yingying Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Zihan Geng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ronghua Zhao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jing Sun
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yanyan Bao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yujing Shi
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Rongmei Yao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shanshan Guo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaolan Cui
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| |
Collapse
|
|
17
|
Coulibaly SDP, Ba B, Mounkoro PP, Diakite B, Kassogue Y, Maiga M, Dara AE, Traoré J, Kamaté Z, Traoré K, Koné M, Maiga B, Diarra Z, Coulibaly S, Togora A, Maiga Y, Koumaré B. Descriptive study of cases of schizophrenia in the Malian population. BMC Psychiatry 2021; 21:413. [PMID: 34416862 PMCID: PMC8377978 DOI: 10.1186/s12888-021-03422-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 08/10/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Schizophrenia is a relatively common disease worldwide with a point prevalence of around 5/1000 in the population. The aim of this present work was to assess the demographic, clinical, familial, and environmental factors associated with schizophrenia in Mali. METHODS This was a prospective descriptive study on a series of 164 patients aged at least 12 years who came for a follow-up consultation at the psychiatry department of the University Hospital Center (CHU) Point G in Mali between February 2019 and January 2020 for schizophrenia spectrum disorder as defined by DSM-5 diagnostic criteria. RESULTS Our results revealed that the male sex was predominant (80.5%). The 25-34 age group was more represented with 44.5%. The place of birth for the majority of our patients was the urban area (52.4%), which also represented the place of the first year of life for the majority of our patients (56.1%). We noted that the unemployed and single people accounted for 56.1 and 61% respectively. More than half of our patients 58.5% reported having reached secondary school level. With the exception of education level, there was a statistically significant difference in the distribution of demographic parameters. Familial schizophrenia cases accounted for 51.7% versus 49.3% for non-familial cases. The different clinical forms were represented by the paranoid form, followed by the undifferentiated form, and the hebephrenic form with respectively 34, 28 and 17.1%. We noted that almost half (48.8%) of patients were born during the cold season. Cannabis use history was not observed in 68.7% of the patients. The proportions of patients with an out-of-school father or an out-of-school mother were 51.2 and 64.2%, respectively. CONCLUSION The onset of schizophrenia in the Malian population has been associated with socio-demographic, clinical, genetic and environmental characteristics.
Collapse
Affiliation(s)
- Souleymane dit Papa Coulibaly
- Faculty of Medicine and Odontostomatology, University of Sciences, Techniques and Technologies of Bamako (USTTB), 1805, Point G, Bamako, Mali
- University Teaching Hospital Point G, Bamako, Mali
| | - Baba Ba
- University Teaching Hospital Point G, Bamako, Mali
| | - Pakuy Pierre Mounkoro
- Faculty of Medicine and Odontostomatology, University of Sciences, Techniques and Technologies of Bamako (USTTB), 1805, Point G, Bamako, Mali
- University Teaching Hospital Point G, Bamako, Mali
| | - Brehima Diakite
- Faculty of Medicine and Odontostomatology, University of Sciences, Techniques and Technologies of Bamako (USTTB), 1805, Point G, Bamako, Mali
- University Teaching Hospital Point G, Bamako, Mali
| | - Yaya Kassogue
- Faculty of Medicine and Odontostomatology, University of Sciences, Techniques and Technologies of Bamako (USTTB), 1805, Point G, Bamako, Mali
- University Teaching Hospital Point G, Bamako, Mali
| | - Mamoudou Maiga
- Faculty of Medicine and Odontostomatology, University of Sciences, Techniques and Technologies of Bamako (USTTB), 1805, Point G, Bamako, Mali
- Institute for Global Health, Northwestern University, Chicago, IL60611 USA
| | | | | | - Zoua Kamaté
- University Teaching Hospital Point G, Bamako, Mali
| | | | | | | | | | - Souleymane Coulibaly
- Faculty of Medicine and Odontostomatology, University of Sciences, Techniques and Technologies of Bamako (USTTB), 1805, Point G, Bamako, Mali
- University Teaching Hospital Point G, Bamako, Mali
| | - Arouna Togora
- Faculty of Medicine and Odontostomatology, University of Sciences, Techniques and Technologies of Bamako (USTTB), 1805, Point G, Bamako, Mali
- University Teaching Hospital Point G, Bamako, Mali
| | - Youssoufa Maiga
- Faculty of Medicine and Odontostomatology, University of Sciences, Techniques and Technologies of Bamako (USTTB), 1805, Point G, Bamako, Mali
- University Teaching Hospital Gabriel Toure, Bamako, Mali
| | - Baba Koumaré
- Faculty of Medicine and Odontostomatology, University of Sciences, Techniques and Technologies of Bamako (USTTB), 1805, Point G, Bamako, Mali
- University Teaching Hospital Point G, Bamako, Mali
| |
Collapse
|
|
18
|
Woods RM, Lorusso JM, Potter HG, Neill JC, Glazier JD, Hager R. Maternal immune activation in rodent models: A systematic review of neurodevelopmental changes in gene expression and epigenetic modulation in the offspring brain. Neurosci Biobehav Rev 2021; 129:389-421. [PMID: 34280428 DOI: 10.1016/j.neubiorev.2021.07.015] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 05/11/2021] [Accepted: 07/11/2021] [Indexed: 01/06/2023]
Abstract
Maternal immune activation (mIA) during pregnancy is hypothesised to disrupt offspring neurodevelopment and predispose offspring to neurodevelopmental disorders such as schizophrenia. Rodent models of mIA have explored possible mechanisms underlying this paradigm and provide a vital tool for preclinical research. However, a comprehensive analysis of the molecular changes that occur in mIA-models is lacking, hindering identification of robust clinical targets. This systematic review assesses mIA-driven transcriptomic and epigenomic alterations in specific offspring brain regions. Across 118 studies, we focus on 88 candidate genes and show replicated changes in expression in critical functional areas, including elevated inflammatory markers, and reduced myelin and GABAergic signalling proteins. Further, disturbed epigenetic markers at nine of these genes support mIA-driven epigenetic modulation of transcription. Overall, our results demonstrate that current outcome measures have direct relevance for the hypothesised pathology of schizophrenia and emphasise the importance of mIA-models in contributing to the understanding of biological pathways impacted by mIA and the discovery of new drug targets.
Collapse
Affiliation(s)
- Rebecca M Woods
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PT, United Kingdom.
| | - Jarred M Lorusso
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Harry G Potter
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Joanna C Neill
- Division of Pharmacy & Optometry, School of Health Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL, United Kingdom
| | - Jocelyn D Glazier
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| | - Reinmar Hager
- Division of Evolution & Genomic Sciences, School of Biological Sciences, Manchester Academic Health Science Center, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PT, United Kingdom
| |
Collapse
|
|
19
|
Watanabe J. Teaching Neuroimmunology to Undergraduate Students: Resource for Full Course or Modular Implementation. JOURNAL OF UNDERGRADUATE NEUROSCIENCE EDUCATION : JUNE : A PUBLICATION OF FUN, FACULTY FOR UNDERGRADUATE NEUROSCIENCE 2021; 19:A163-A184. [PMID: 34552435 PMCID: PMC8437358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Indexed: 06/13/2023]
Abstract
This paper describes a course I designed to teach neuroimmunology to undergraduate students. In this course I incorporated many active learning strategies to help make it a student-centered class, where they developed communication skills, while reading and analyzing primary literature articles. As the field of neuroimmunology is relatively new, most textbooks in the field approached the subject from the perspective of neurology and autoimmune diseases. Therefore, I used reading, analysis, and student-led presentation of primary papers in the classroom to not only develop critical thinking and application of the scientific method, but also oral communication skills. Other activities such as writing New York Times-style articles and literature review papers were employed to develop written communications skills. The goal of this article is to provide a reference tool for instructors trained in neuroscience to deploy an entire course on neuroimmunology or select a module or a single paper to incorporate into their existing course to offer students a taste for neuroimmunology.
Collapse
|
|
20
|
MacDowell KS, Munarriz-Cuezva E, Meana JJ, Leza JC, Ortega JE. Paliperidone Reversion of Maternal Immune Activation-Induced Changes on Brain Serotonin and Kynurenine Pathways. Front Pharmacol 2021; 12:682602. [PMID: 34054556 PMCID: PMC8156415 DOI: 10.3389/fphar.2021.682602] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 04/30/2021] [Indexed: 12/23/2022] Open
Abstract
Emerging evidence indicates that early-life exposure to environmental factors may increase the risk for schizophrenia via inflammatory mechanisms. Inflammation can alter the metabolism of tryptophan through the oxidative kynurenine pathway to compounds with neurotoxic and neuroprotective activity and compromise serotonin (5-HT) synthesis. Here we investigate the role of serotonergic and kynurenine pathways in the maternal immune activation (MIA) animal model of schizophrenia. The potential reversion exerted by long-term antipsychotic treatment was also evaluated. MIA was induced by prenatal administration of polyinosinic:polycytidylic acid (poly (I:C)) in mice. Expression of different proteins and the content of different metabolites involved in the function of serotonergic and kynurenine pathways was assessed by RT-PCR, immunoblot and ELISA analyses in frontal cortex of the offspring after puberty. MIA decreased tissue 5-HT content and promoted changes in the expression of serotonin transporter, 5-HT2A and 5-HT2C receptors. Expression of indoleamine 2,3-dioxygenase 2 (IDO2) and kynurenine 3-monooxygenase (KMO) was increased by poly (I:C) whereas kynurenine aminotransferase II and its metabolite kynurenic acid were not altered. Long-term paliperidone was able to counteract MIA-induced changes in 5-HT and KMO, and to increase tryptophan availability and tryptophan hydroxylase-2 expression in poly (I:C) mice but not in controls. MIA-induced increase of the cytotoxic risk ratio of kynurenine metabolites (quinolinic/kynurenic acid) was also reversed by paliperidone. MIA induces specific long-term brain effects on serotonergic activity. Such effects seem to be related with alternative activation of the kynurenine metabolic pathway towards a cytotoxic status. Atypical antipsychotic paliperodine partially remediates abnormalities observed after MIA.
Collapse
Affiliation(s)
- Karina S MacDowell
- Department of Pharmacology and Toxicology, Faculty of Medicine, University Complutense of Madrid (UCM), Madrid, Spain.,Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Bizkaia, Madrid, Spain.,Instituto de Investigación Hospital 12 de Octubre (i+12), IUIN-UCM, Madrid, Spain
| | - Eva Munarriz-Cuezva
- Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Bizkaia, Madrid, Spain.,Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain
| | - J Javier Meana
- Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Bizkaia, Madrid, Spain.,Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.,Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Juan C Leza
- Department of Pharmacology and Toxicology, Faculty of Medicine, University Complutense of Madrid (UCM), Madrid, Spain.,Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Bizkaia, Madrid, Spain.,Instituto de Investigación Hospital 12 de Octubre (i+12), IUIN-UCM, Madrid, Spain
| | - Jorge E Ortega
- Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Bizkaia, Madrid, Spain.,Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.,Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain
| |
Collapse
|
|
21
|
Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders. Pharmaceuticals (Basel) 2021; 14:ph14040340. [PMID: 33917837 PMCID: PMC8068239 DOI: 10.3390/ph14040340] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 12/19/2022] Open
Abstract
Neurobehavioral alterations and cognitive impairment are common phenomena that represent neuropsychiatric disorders and can be triggered by an exacerbated immune response against pathogens, brain injury, or autoimmune diseases. Pro-inflammatory molecules, such as cytokines and chemokines, are produced in the brain by resident cells, mainly by microglia and astrocytes. Brain infiltrating immune cells constitutes another source of these molecules, contributing to an impaired neurological synapse function, affecting typical neurobehavioral and cognitive performance. Currently, there is increasing evidence supporting the notion that behavioral alterations and cognitive impairment can be associated with respiratory viral infections, such as human respiratory syncytial virus, influenza, and SARS-COV-2, which are responsible for endemic, epidemic, or pandemic outbreak mainly in the winter season. This article will review the brain′s pro-inflammatory response due to infection by three highly contagious respiratory viruses that are the leading cause of acute respiratory illness, morbidity, and mobility in infants, immunocompromised and elderly population. How these respiratory viral pathogens induce increased secretion of pro-inflammatory molecules and their relationship with the alterations at a behavioral and cognitive level will be discussed.
Collapse
|
|
22
|
Tiwari P, Fanibunda SE, Kapri D, Vasaya S, Pati S, Vaidya VA. GPCR signaling: role in mediating the effects of early adversity in psychiatric disorders. FEBS J 2021; 288:2602-2621. [DOI: 10.1111/febs.15738] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/11/2021] [Accepted: 01/27/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Praachi Tiwari
- Department of Biological Sciences Tata Institute of Fundamental Research Mumbai India
| | - Sashaina E. Fanibunda
- Department of Biological Sciences Tata Institute of Fundamental Research Mumbai India
- Medical Research Centre Kasturba Health Society Mumbai India
| | - Darshana Kapri
- Department of Biological Sciences Tata Institute of Fundamental Research Mumbai India
| | - Shweta Vasaya
- Department of Biological Sciences Tata Institute of Fundamental Research Mumbai India
| | - Sthitapranjya Pati
- Department of Biological Sciences Tata Institute of Fundamental Research Mumbai India
| | - Vidita A. Vaidya
- Department of Biological Sciences Tata Institute of Fundamental Research Mumbai India
| |
Collapse
|
|
23
|
Dong E, Pandey SC. Prenatal stress induced chromatin remodeling and risk of psychopathology in adulthood. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 156:185-215. [PMID: 33461663 PMCID: PMC7864549 DOI: 10.1016/bs.irn.2020.08.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
New insights into the pathophysiology of psychiatric disorders suggest the existence of a complex interplay between genetics and environment. This notion is supported by evidence suggesting that exposure to stress during pregnancy exerts profound effects on the neurodevelopment and behavior of the offspring and predisposes them to psychiatric disorders later in life. Accumulated evidence suggests that vulnerability to psychiatric disorders may result from permanent negative effects of long-term changes in synaptic plasticity due to altered epigenetic mechanisms (histone modifications and DNA methylation) that lead to condensed chromatin architecture, thereby decreasing the expression of candidate genes during early brain development. In this chapter, we have summarized the literature of clinical studies on psychiatric disorders induced by maternal stress during pregnancy. We also discussed the epigenetic alterations of gene regulations induced by prenatal stress. Because the clinical manifestations of psychiatric disorders are complex, it is obvious that the biological progression of these diseases cannot be studied only in postmortem brains of patients and the use of animal models is required. Therefore, in this chapter, we have introduced a well-established mouse model of prenatal stress (PRS) generated in restrained pregnant dams. The behavioral phenotypes of the offspring (PRS mice) born to the stressed dam and underlying epigenetic changes in key molecules related to synaptic activity were described and highlighted. PRS mice may serve as a useful model for investigating the pathogenesis of psychiatric disorders and may be a useful tool for screening for the potential compounds that may normalize aberrant epigenetic mechanisms induced by prenatal stress.
Collapse
Affiliation(s)
- Erbo Dong
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States.
| | - Subhash C Pandey
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States; Jesse Brown VA Medical Center, Chicago, IL, United States
| |
Collapse
|
|
24
|
Pati S, Saba K, Salvi SS, Tiwari P, Chaudhari PR, Verma V, Mukhopadhyay S, Kapri D, Suryavanshi S, Clement JP, Patel AB, Vaidya VA. Chronic postnatal chemogenetic activation of forebrain excitatory neurons evokes persistent changes in mood behavior. eLife 2020; 9:56171. [PMID: 32955432 PMCID: PMC7652419 DOI: 10.7554/elife.56171] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 09/18/2020] [Indexed: 12/19/2022] Open
Abstract
Early adversity is a risk factor for the development of adult psychopathology. Common across multiple rodent models of early adversity is increased signaling via forebrain Gq-coupled neurotransmitter receptors. We addressed whether enhanced Gq-mediated signaling in forebrain excitatory neurons during postnatal life can evoke persistent mood-related behavioral changes. Excitatory hM3Dq DREADD-mediated chemogenetic activation of forebrain excitatory neurons during postnatal life (P2–14), but not in juvenile or adult windows, increased anxiety-, despair-, and schizophrenia-like behavior in adulthood. This was accompanied by an enhanced metabolic rate of cortical and hippocampal glutamatergic and GABAergic neurons. Furthermore, we observed reduced activity and plasticity-associated marker expression, and perturbed excitatory/inhibitory currents in the hippocampus. These results indicate that Gq-signaling-mediated activation of forebrain excitatory neurons during the critical postnatal window is sufficient to program altered mood-related behavior, as well as functional changes in forebrain glutamate and GABA systems, recapitulating aspects of the consequences of early adversity. Stress and adversity in early childhood can have long-lasting effects, predisposing people to mental illness and mood disorders in adult life. The weeks immediately before and after birth are critical for establishing key networks of neurons in the brain. Therefore, any disruption to these neural circuits during this time can be detrimental to emotional development. However, it is still unclear which cellular mechanisms cause these lasting changes in behavior. Studies in animals suggest that these long-term effects could result from abnormalities in a few signaling pathways in the brain. For example, it has been proposed that overstimulating the cells that activate circuits in the forebrain – also known as excitatory neurons – may contribute to the behavioral changes that persist into adulthood. To test this theory, Pati et al. used genetic engineering to modulate a signaling pathway in male mice, which is known to stimulate excitatory neurons in the forebrain. The experiments showed that prolonged activation of excitatory neurons in the first two weeks after birth resulted in anxious and despair-like behaviors as the animals aged. The mice also displayed discrepancies in how they responded to certain external sensory information, which is a hallmark of schizophrenia-like behavior. However, engineering the same changes in adolescent and adult mice had no effect on their mood-related behaviors. This animal study reinforces just how critical the first few weeks of life are for optimal brain development. It provides an insight into a possible mechanism of how disruption during this time could alter emotional behavior. The findings are also relevant to psychiatrists interested in the underlying causes of mental illness after early childhood adversity.
Collapse
Affiliation(s)
- Sthitapranjya Pati
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Kamal Saba
- Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Sonali S Salvi
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Praachi Tiwari
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Pratik R Chaudhari
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Vijaya Verma
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
| | - Sourish Mukhopadhyay
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Darshana Kapri
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Shital Suryavanshi
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - James P Clement
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
| | - Anant B Patel
- Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Vidita A Vaidya
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| |
Collapse
|
|
25
|
Ibi D, Nakasai G, Koide N, Sawahata M, Kohno T, Takaba R, Nagai T, Hattori M, Nabeshima T, Yamada K, Hiramatsu M. Reelin Supplementation Into the Hippocampus Rescues Abnormal Behavior in a Mouse Model of Neurodevelopmental Disorders. Front Cell Neurosci 2020; 14:285. [PMID: 32982694 PMCID: PMC7492784 DOI: 10.3389/fncel.2020.00285] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 08/11/2020] [Indexed: 12/19/2022] Open
Abstract
In the majority of schizophrenia patients, chronic atypical antipsychotic administration produces a significant reduction in or even complete remission of psychotic symptoms such as hallucinations and delusions. However, these drugs are not effective in improving cognitive and emotional deficits in patients with schizophrenia. Atypical antipsychotic drugs have a high affinity for the dopamine D2 receptor, and a modest affinity for the serotonin 5-HT2A receptor. The cognitive and emotional deficits in schizophrenia are thought to involve neural networks beyond the classical dopaminergic mesolimbic pathway, however, including serotonergic systems. For example, mutations in the RELN gene, which encodes Reelin, an extracellular matrix protein involved in neural development and synaptic plasticity, are associated with neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. Furthermore, hippocampal Reelin levels are down-regulated in the brains of both schizophrenic patients and in rodent models of schizophrenia. In the present study, we investigated the effect of Reelin microinjection into the mouse hippocampus on behavioral phenotypes to evaluate the role of Reelin in neurodevelopmental disorders and to test a therapeutic approach that extends beyond classical monoamine targets. To model the cognitive and emotional deficits, as well as histological decreases in Reelin-positive cell numbers and hippocampal synaptoporin distribution, a synaptic vesicle protein, offspring that were prenatally exposed to maternal immune activation were used. Microinjections of recombinant Reelin protein into the hippocampus rescued impairments in object memory and anxiety-like behavior and recruited synaptoporin in the hippocampus in offspring exposed to antenatal inflammation. These results suggest that Reelin supplementation has the potential to treat cognitive and emotional impairments, as well as synaptic disturbances, in patients with neurodevelopmental disorders such as schizophrenia.
Collapse
Affiliation(s)
- Daisuke Ibi
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Genki Nakasai
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Nayu Koide
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Masahito Sawahata
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takao Kohno
- Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
| | - Rika Takaba
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Taku Nagai
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Project Office for Neuropsychological Research Center, Fujita Health University, Toyoake, Japan
| | - Mitsuharu Hattori
- Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
| | - Toshitaka Nabeshima
- Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Toyoake, Japan
| | - Kiyofumi Yamada
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masayuki Hiramatsu
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| |
Collapse
|
|
26
|
Saunders JM, Moreno JL, Ibi D, Sikaroodi M, Kang DJ, Muñoz-Moreno R, Dalmet SS, García-Sastre A, Gillevet PM, Dozmorov MG, Bajaj JS, González-Maeso J. Gut microbiota manipulation during the prepubertal period shapes behavioral abnormalities in a mouse neurodevelopmental disorder model. Sci Rep 2020; 10:4697. [PMID: 32170216 PMCID: PMC7070045 DOI: 10.1038/s41598-020-61635-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 03/02/2020] [Indexed: 02/08/2023] Open
Abstract
Previous studies demonstrate an association between activation of the maternal immune system during pregnancy and increased risk of neurodevelopmental psychiatric conditions, such as schizophrenia and autism, in the offspring. Relatively recent findings also suggest that the gut microbiota plays an important role in shaping brain development and behavior. Here we show that maternal immune activation (MIA) accomplished by infection with a mouse-adapted influenza virus during pregnancy induced up-regulation of frontal cortex serotonin 5-HT2A receptor (5-HT2AR) density in the adult offspring, a phenotype previously observed in postmortem frontal cortex of schizophrenic subjects. 5-HT2AR agonist-induced head-twitch behavior was also augmented in this preclinical mouse model. Using the novel object recognition (NOR) test to evaluate cognitive performance, we demonstrate that MIA induced NOR deficits in adult offspring. Oral antibiotic treatment of prepubertal mice prevented this cognitive impairment, but not increased frontal cortex 5-HT2AR density or psychedelic-induced head-twitch behavior in adult MIA offspring. Additionally, gut microbiota transplantation from MIA mice produced behavioral deficits in antibiotic-treated mock mice. Adult MIA offspring displayed altered gut microbiota, and relative abundance of specific components of the gut microbiota, including Ruminococcaceae, correlated with frontal cortex 5-HT2AR density. Together, these findings provide a better understanding of basic mechanisms by which prenatal insults impact offspring brain function, and suggest gut-brain axis manipulation as a potential therapeutic approach for neurodevelopmental psychiatric conditions.
Collapse
Affiliation(s)
- Justin M Saunders
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - José L Moreno
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.,VIVEbiotech S.L., E-20009, Donostia/San Sebastián, Spain
| | - Daisuke Ibi
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.,Department of Chemical Pharmacology, Meijo University, Nagoya, 468-8503, Japan
| | - Masoumeh Sikaroodi
- Center for Microbiome Analysis, George Mason University, Manassas, VA, 20110, USA
| | - Dae Joong Kang
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, 23298, USA
| | - Raquel Muñoz-Moreno
- Department of Microbiology and Global Health & Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Swati S Dalmet
- Center for Microbiome Analysis, George Mason University, Manassas, VA, 20110, USA
| | - Adolfo García-Sastre
- Department of Microbiology and Global Health & Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Department of Medicine - Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Patrick M Gillevet
- Center for Microbiome Analysis, George Mason University, Manassas, VA, 20110, USA
| | - Mikhail G Dozmorov
- Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, 23298, USA
| | - Javier González-Maeso
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.
| |
Collapse
|
|
27
|
Kępińska AP, Iyegbe CO, Vernon AC, Yolken R, Murray RM, Pollak TA. Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk. Front Psychiatry 2020; 11:72. [PMID: 32174851 PMCID: PMC7054463 DOI: 10.3389/fpsyt.2020.00072] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 01/28/2020] [Indexed: 12/13/2022] Open
Abstract
Associations between influenza infection and psychosis have been reported since the eighteenth century, with acute "psychoses of influenza" documented during multiple pandemics. In the late 20th century, reports of a season-of-birth effect in schizophrenia were supported by large-scale ecological and sero-epidemiological studies suggesting that maternal influenza infection increases the risk of psychosis in offspring. We examine the evidence for the association between influenza infection and schizophrenia risk, before reviewing possible mechanisms via which this risk may be conferred. Maternal immune activation models implicate placental dysfunction, disruption of cytokine networks, and subsequent microglial activation as potentially important pathogenic processes. More recent neuroimmunological advances focusing on neuronal autoimmunity following infection provide the basis for a model of infection-induced psychosis, potentially implicating autoimmunity to schizophrenia-relevant protein targets including the N-methyl-D-aspartate receptor. Finally, we outline areas for future research and relevant experimental approaches and consider whether the current evidence provides a basis for the rational development of strategies to prevent schizophrenia.
Collapse
Affiliation(s)
- Adrianna P. Kępińska
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Conrad O. Iyegbe
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Anthony C. Vernon
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
| | - Robert Yolken
- Stanley Laboratory of Developmental Neurovirology, Johns Hopkins Medical Center, Baltimore, MD, United States
| | - Robin M. Murray
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Thomas A. Pollak
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| |
Collapse
|
|
28
|
Knutson AO, Watters JJ. All roads lead to inflammation: Is maternal immune activation a common culprit behind environmental factors impacting offspring neural control of breathing? Respir Physiol Neurobiol 2019; 274:103361. [PMID: 31874263 DOI: 10.1016/j.resp.2019.103361] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 12/14/2019] [Accepted: 12/19/2019] [Indexed: 12/12/2022]
Abstract
Despite numerous studies investigating how prenatal exposures impact the developing brain, there remains very little known about how these in utero exposures impact the life-sustaining function of breathing. While some exposures such as alcohol and drugs of abuse are well-known to alter respiratory function, few studies have evaluated other common maternal environmental stimuli, such as maternal infection, inhalation of diesel exhaust particles prevalent in urban areas, or obstructive sleep apnea during pregnancy, just to name a few. The goals of this review article are thus to: 1) highlight data on gestational exposures that impair respiratory function, 2) discuss what is known about the potential role of inflammation in the effects of these maternal exposures, and 3) identify less studied but potential in utero exposures that could negatively impact CNS regions important in respiratory motor control, perhaps by impacting maternal or fetal inflammation. We highlight gaps in knowledge, summarize evidence related to the possible contributions of inflammation, and discuss the need for further studies of life-long offspring respiratory function both at baseline and after respiratory challenge.
Collapse
Affiliation(s)
- Andrew O Knutson
- Molecular and Environmental Toxicology Training Program and Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, United States
| | - Jyoti J Watters
- Molecular and Environmental Toxicology Training Program and Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, United States.
| |
Collapse
|
|
29
|
García-Bea A, Miranda-Azpiazu P, Muguruza C, Marmolejo-Martinez-Artesero S, Diez-Alarcia R, Gabilondo AM, Callado LF, Morentin B, González-Maeso J, Meana JJ. Serotonin 5-HT 2A receptor expression and functionality in postmortem frontal cortex of subjects with schizophrenia: Selective biased agonism via G αi1-proteins. Eur Neuropsychopharmacol 2019; 29:1453-1463. [PMID: 31734018 DOI: 10.1016/j.euroneuro.2019.10.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/17/2019] [Accepted: 10/29/2019] [Indexed: 12/20/2022]
Abstract
Serotonin 5-HT2A receptors (5-HT2ARs) have been implicated in schizophrenia. However, postmortem studies on 5-HT2ARs expression and functionality in schizophrenia are scarce. The 5-HT2AR mRNA and immunoreactive protein expression were evaluated in postmortem tissue from dorsolateral prefrontal cortex (DLPFC) of antipsychotic-free (n = 18) and antipsychotic-treated (n = 9) subjects with schizophrenia, and matched controls (n = 27). Functional coupling of 5-HT2AR to G-proteins was tested by measuring the activation induced by the agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride ((±)DOI) in antibody-capture [35S]GTPγS scintillation proximity assays (SPA). In antipsychotic-free schizophrenia subjects, 5-HT2AR mRNA expression and protein immunoreactivity in total homogenates was similar to controls. In contrast, in antipsychotic-treated schizophrenia subjects, lower mRNA expression (60±9% vs controls) and a trend to reduced protein immunoreactivity (86±5% vs antipsychotic-free subjects) just in membrane-enriched fractions was observed. [35S]GTPγS SPA revealed a significant ~6% higher stimulation of Gαi1-protein by (±)DOI in schizophrenia, whereas activation of the canonical Gαq/11-protein pathway by (±)DOI remained unchanged. Expression of Gαi1- and Gαq/11-proteins did not differ between groups. Accordingly, in rats chronically treated with clozapine, but not with haloperidol, a 30-40% reduction was observed in 5-HT2AR mRNA expression, 5-HT2AR protein immunoreactivity and [3H]ketanserin binding in brain cortical membranes. Overall, the data suggest a supersensitive 5-HT2AR signaling through inhibitory Gαi1-proteins in schizophrenia. Together with previous results, a dysfunctional pro-hallucinogenic agonist-sensitive 5-HT2AR conformation in postmortem DLPFC of subjects with schizophrenia is proposed. Atypical antipsychotic treatment would contribute to counterbalance this 5-HT2AR supersensitivity by reducing receptor expression.
Collapse
Affiliation(s)
- Aintzane García-Bea
- Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain
| | - Patricia Miranda-Azpiazu
- Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain
| | - Carolina Muguruza
- Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain
| | | | - Rebeca Diez-Alarcia
- Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain; Biocruces Bizkaia Health Research Institute, Spain
| | - Ane M Gabilondo
- Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain; Biocruces Bizkaia Health Research Institute, Spain
| | - Luis F Callado
- Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain; Biocruces Bizkaia Health Research Institute, Spain
| | - Benito Morentin
- Biocruces Bizkaia Health Research Institute, Spain; Basque Institute of Legal Medicine, Spain
| | - Javier González-Maeso
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, VA, USA
| | - J Javier Meana
- Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain; Biocruces Bizkaia Health Research Institute, Spain.
| |
Collapse
|
|
30
|
Cook JR, Platek SM, Espinoza CN. Proposed symptom-based model of the origins of schizophrenia. Med Hypotheses 2019; 134:109428. [PMID: 31678901 DOI: 10.1016/j.mehy.2019.109428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/03/2019] [Accepted: 10/10/2019] [Indexed: 10/25/2022]
Abstract
Schizophrenia is considered a severe mental illness and effects an estimated 1% of the world population. The evidence suggests that incidence rate has been and will continue to be stable over time. Here we adopt a symptomatology-focused evolutionary informed approach to discuss the possible biological adaptations of various presentations of schizophrenia. It is our contention that rather than thinking about schizophrenia as a single disorder, or even a spectrum of disorders, marked by social maladaptation and personal subjective distress, that an evolutionary interpretation based on adaptive nature of individual, or small clusters of, symptoms could prove to be more useful in better understanding the pathophysiology of schizophrenia and its relationship with other psychiatric diagnoses.
Collapse
|
|
31
|
de la Fuente Revenga M, Shin JM, Vohra HZ, Hideshima KS, Schneck M, Poklis JL, González-Maeso J. Fully automated head-twitch detection system for the study of 5-HT 2A receptor pharmacology in vivo. Sci Rep 2019; 9:14247. [PMID: 31582824 PMCID: PMC6776537 DOI: 10.1038/s41598-019-49913-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 08/30/2019] [Indexed: 01/29/2023] Open
Abstract
Head-twitch behavior (HTR) is the behavioral signature of psychedelic drugs upon stimulation of the serotonin 5-HT2A receptor (5-HT2AR) in rodents. Following the previous report of a semi-automated detection of HTR based on the dynamics of mouse's head movement, here we present a system for the identification of individual HTR events in a fully automated fashion. The validity of this fully automated HTR detection system was tested with the psychedelic drug DOI in 5-HT2AR-KO mice, and via evaluation of potential sources of false-positive and false-negative HTR events. The increased throughput in data processing achieved via automation afforded the possibility of conducting otherwise time consuming HTR time-course studies. To further assess the versatility of our system, we also explored the pharmacological interactions between 5-HT2AR and the metabotropic glutamate receptor 2 (mGluR2). Our data demonstrate the potentiation effect of the mGluR2/3 antagonist LY341495 on DOI-induced HTR, as well as the HTR-blocking effect of the mGluR2/3 agonist and antipsychotic drug in development LY404039. This fully automated system can contribute to speed up our understanding of 5-HT2AR's pharmacology and its characteristic behavioral outputs in rodents.
Collapse
Affiliation(s)
- Mario de la Fuente Revenga
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - Jong M Shin
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - Hiba Z Vohra
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - Kelsey S Hideshima
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - Matthew Schneck
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.,Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, 23220, USA
| | - Justin L Poklis
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Javier González-Maeso
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.
| |
Collapse
|
|
32
|
Sheu JR, Hsieh CY, Jayakumar T, Tseng MF, Lee HN, Huang SW, Manubolu M, Yang CH. A Critical Period for the Development of Schizophrenia-Like Pathology by Aberrant Postnatal Neurogenesis. Front Neurosci 2019; 13:635. [PMID: 31275109 PMCID: PMC6591536 DOI: 10.3389/fnins.2019.00635] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 06/03/2019] [Indexed: 11/18/2022] Open
Abstract
Schizophrenia is a complex and serious mental disorder, and patients with schizophrenia are characterized by psychological hallucinations, deregulated emotionality, and cognitive impairment. Evidence indicated that postnatal neurogenesis in the hippocampus is profoundly impaired in schizophrenic individuals but the role of such dysregulated neurodevelopmental processing in the pathophysiological progress of schizophrenia has not been well investigated. Here in this study, by using the rodent model of schizophrenia through maternal immune activation of poly (I:C) injection, we aimed to examine whether the postnatal neurogenesis might be involved in the development of schizophrenia-like pathology. Through the comprehensive behavioral analyses of multiple core symptoms of schizophrenia at different developmental stages (6-, 9-, and 12-weeks after birth) of the affected offspring, we found a delayed onset of schizophrenia-like behaviors in poly (I:C) animals through the development. Meanwhile, there is an age-dependent alteration of postnatal neurogenesis in the poly (I:C) animals along different development stages by which the aberrant dendritic elaboration functionally correlated with the schizophrenia-like symptoms in 9-week-old of age for the animals. Interestingly, increase in the neurogenesis during a critical period of neurodevelopment exacerbates the schizophrenia-like pathology. Conversely, temporal suppression of aberrant postnatal neurogenesis during the same period of neurodevelopment ameliorates the occurrence of schizophrenia-like symptoms. Together, these findings strongly suggested the aberrant dendritic growth of postnatal neurogenesis during the critical time window of development is essential for controlling the pathophysiological progression of schizophrenia-like symptoms. And pharmacological treatments that adjust these abnormalities may provide potential therapeutic benefits toward patients with schizophrenia in clinic.
Collapse
Affiliation(s)
- Joen-Rong Sheu
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Ying Hsieh
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Thanasekaran Jayakumar
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Mei-Fang Tseng
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsing-Ni Lee
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shin-Wei Huang
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Manjunath Manubolu
- Department of Evolution, Ecology and Organismal Biology, The Ohio State University, Columbus, OH, United States
| | - Chih-Hao Yang
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| |
Collapse
|
|
33
|
Amato D, Kruyer A, Samaha AN, Heinz A. Hypofunctional Dopamine Uptake and Antipsychotic Treatment-Resistant Schizophrenia. Front Psychiatry 2019; 10:314. [PMID: 31214054 PMCID: PMC6557273 DOI: 10.3389/fpsyt.2019.00314] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 04/23/2019] [Indexed: 01/07/2023] Open
Abstract
Antipsychotic treatment resistance in schizophrenia remains a major issue in psychiatry. Nearly 30% of patients with schizophrenia do not respond to antipsychotic treatment, yet the underlying neurobiological causes are unknown. All effective antipsychotic medications are thought to achieve their efficacy by targeting the dopaminergic system. Here we review early literature describing the fundamental mechanisms of antipsychotic drug efficacy, highlighting mechanistic concepts that have persisted over time. We then reconsider the original framework for understanding antipsychotic efficacy in light of recent advances in our scientific understanding of the dopaminergic effects of antipsychotics. Based on these new insights, we describe a role for the dopamine transporter in the genesis of both antipsychotic therapeutic response and primary resistance. We believe that this discussion will help delineate the dopaminergic nature of antipsychotic treatment-resistant schizophrenia.
Collapse
Affiliation(s)
- Davide Amato
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, United States
| | - Anna Kruyer
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, United States
| | - Anne-Noël Samaha
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
| | - Andreas Heinz
- Department of Psychiatry, Charité University Medicine Berlin, Campus Charité Mitte, Berlin, Germany
| |
Collapse
|
|
34
|
Hernandez L. ADSA Foundation Scholar Award: A role for serotonin in lactation physiology—Where do we go from here? J Dairy Sci 2018; 101:5671-5678. [DOI: 10.3168/jds.2018-14562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 03/21/2018] [Indexed: 12/13/2022]
|
|
35
|
Investigating the neuroimmunogenic architecture of schizophrenia. Mol Psychiatry 2018; 23:1251-1260. [PMID: 28485405 DOI: 10.1038/mp.2017.89] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 01/29/2017] [Accepted: 03/08/2017] [Indexed: 12/13/2022]
Abstract
The role of the immune system in schizophrenia remains controversial despite numerous studies to date. Most studies have profiled expression of select genes or proteins in peripheral blood, but none have focused on the expression of canonical pathways that mediate overall immune response. The current study used a systematic genetic approach to investigate the role of the immune system in a large sample of post-mortem brain of patients with schizophrenia: RNA sequencing was performed to assess the differential expression of 561 immune genes and 20 immune pathways in dorsolateral prefrontal cortex (DLPFC) (144 schizophrenia and 196 control subjects) and hippocampus (83 schizophrenia and 187 control subjects). The effect of RNA quality on gene expression was found to be highly correlated with the effect of diagnosis even after adjustment for observable RNA quality parameters (i.e. RNA integrity), thus this confounding relationship was statistically controlled using principal components derived from the gene expression matrix. In DLPFC, 23 immune genes were found to be differentially expressed (false discovery rate <0.05), of which seven genes replicated in both directionality and at nominal significance (P<0.05) in an independent post-mortem DLPFC data set (182 schizophrenia and 212 control subjects), although notably at least five of these genes have prominent roles in pathways other than immune function and overall the effect sizes were minimal (fold change <1.1). In the hippocampus, no individual immune genes were identified to be differentially expressed, and in both DLPFC and hippocampus none of the individual immune pathways were relatively differentially expressed. Further, genomic schizophrenia risk profiles scores were not correlated with the expression of individual immune pathways or differentially expressed genes. Overall, past reports claiming a primary pathogenic role of the immune system intrinsic to the brain in schizophrenia could not be confirmed.
Collapse
|
|
36
|
Solek CM, Farooqi N, Verly M, Lim TK, Ruthazer ES. Maternal immune activation in neurodevelopmental disorders. Dev Dyn 2017; 247:588-619. [PMID: 29226543 DOI: 10.1002/dvdy.24612] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 11/30/2017] [Accepted: 12/01/2017] [Indexed: 12/12/2022] Open
Abstract
Converging lines of evidence from basic science and clinical studies suggest a relationship between maternal immune activation (MIA) and neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. The mechanisms through which MIA increases the risk of neurodevelopmental disorders have become a subject of intensive research. This review aims to describe how dysregulation of microglial function and immune mechanisms may link MIA and neurodevelopmental pathologies. We also summarize the current evidence in animal models of MIA. Developmental Dynamics 247:588-619, 2018. © 2017 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Cynthia M Solek
- Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Nasr Farooqi
- Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Myriam Verly
- Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Tony K Lim
- Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Edward S Ruthazer
- Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| |
Collapse
|
|
37
|
Lopez-Gimenez JF, de la Fuente Revenga M, Ruso-Julve F, Saunders JM, Moreno JL, Crespo-Facorro B, González-Maeso J. Validation of schizophrenia gene expression profile in a preclinical model of maternal infection during pregnancy. Schizophr Res 2017; 189:217-218. [PMID: 28202291 PMCID: PMC5554460 DOI: 10.1016/j.schres.2017.02.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 01/30/2017] [Accepted: 02/02/2017] [Indexed: 11/20/2022]
Affiliation(s)
- Juan F Lopez-Gimenez
- Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC-CSIC), Santander, Spain; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA.
| | - Mario de la Fuente Revenga
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA
| | - Fulgencio Ruso-Julve
- University Hospital Marqués de Valdecilla, IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Santander, Spain
| | - Justin M Saunders
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA
| | - José L Moreno
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA
| | - Benedicto Crespo-Facorro
- University Hospital Marqués de Valdecilla, IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Santander, Spain; CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Santander, Spain
| | - Javier González-Maeso
- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA.
| |
Collapse
|
|
38
|
Pelkey KA, Chittajallu R, Craig MT, Tricoire L, Wester JC, McBain CJ. Hippocampal GABAergic Inhibitory Interneurons. Physiol Rev 2017; 97:1619-1747. [PMID: 28954853 PMCID: PMC6151493 DOI: 10.1152/physrev.00007.2017] [Citation(s) in RCA: 569] [Impact Index Per Article: 71.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 05/16/2017] [Accepted: 05/26/2017] [Indexed: 12/11/2022] Open
Abstract
In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10-15% of the total neuronal population; however, their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and circuit function. Here we provide an overview of the current state of the field of interneuron research, focusing largely on the hippocampus. We discuss recent advances related to the various cell types, including their development and maturation, expression of subtype-specific voltage- and ligand-gated channels, and their roles in network oscillations. We also discuss recent technological advances and approaches that have permitted high-resolution, subtype-specific examination of their roles in numerous neural circuit disorders and the emerging therapeutic strategies to ameliorate such pathophysiological conditions. The ultimate goal of this review is not only to provide a touchstone for the current state of the field, but to help pave the way for future research by highlighting where gaps in our knowledge exist and how a complete appreciation of their roles will aid in future therapeutic strategies.
Collapse
Affiliation(s)
- Kenneth A Pelkey
- Porter Neuroscience Center, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, University of Exeter, Exeter, United Kingdom; and Sorbonne Universités, UPMC University of Paris, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine, Paris, France
| | - Ramesh Chittajallu
- Porter Neuroscience Center, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, University of Exeter, Exeter, United Kingdom; and Sorbonne Universités, UPMC University of Paris, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine, Paris, France
| | - Michael T Craig
- Porter Neuroscience Center, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, University of Exeter, Exeter, United Kingdom; and Sorbonne Universités, UPMC University of Paris, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine, Paris, France
| | - Ludovic Tricoire
- Porter Neuroscience Center, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, University of Exeter, Exeter, United Kingdom; and Sorbonne Universités, UPMC University of Paris, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine, Paris, France
| | - Jason C Wester
- Porter Neuroscience Center, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, University of Exeter, Exeter, United Kingdom; and Sorbonne Universités, UPMC University of Paris, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine, Paris, France
| | - Chris J McBain
- Porter Neuroscience Center, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, University of Exeter, Exeter, United Kingdom; and Sorbonne Universités, UPMC University of Paris, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine, Paris, France
| |
Collapse
|
|
39
|
Perinatal inflammation and adult psychopathology: From preclinical models to humans. Semin Cell Dev Biol 2017; 77:104-114. [PMID: 28890420 DOI: 10.1016/j.semcdb.2017.09.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Revised: 08/22/2017] [Accepted: 09/06/2017] [Indexed: 02/05/2023]
Abstract
Perinatal environment plays a crucial role in brain development and determines its function through life. Epidemiological studies and clinical reports link perinatal exposure to infection and/or immune activation to various psychiatric disorders. In addition, accumulating evidence from animal models shows that perinatal inflammation can affect various behaviors relevant to psychiatric disorders such as schizophrenia, autism, anxiety and depression. Remarkably, the effects on behavior and brain function do not always depend on the type of inflammatory stimulus or the perinatal age targeted, so diverse inflammatory events can have similar consequences on the brain. Moreover, other perinatal environmental factors that affect behavior (e.g. diet and stress) also elicit inflammatory responses. Understanding the interplay between perinatal environment and inflammation on brain development is required to identify the mechanisms through which perinatal inflammation affect brain function in the adult animal. Evidence for the role of the peripheral immune system and glia on perinatal programming of behavior is discussed in this review, along with recent evidence for the role of epigenetic mechanisms affecting gene expression in the brain.
Collapse
|
|
40
|
Mottahedin A, Ardalan M, Chumak T, Riebe I, Ek J, Mallard C. Effect of Neuroinflammation on Synaptic Organization and Function in the Developing Brain: Implications for Neurodevelopmental and Neurodegenerative Disorders. Front Cell Neurosci 2017; 11:190. [PMID: 28744200 PMCID: PMC5504097 DOI: 10.3389/fncel.2017.00190] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 06/20/2017] [Indexed: 12/27/2022] Open
Abstract
The brain is a plastic organ where both the intrinsic CNS milieu and extrinsic cues play important roles in shaping and wiring neural connections. The perinatal period constitutes a critical time in central nervous system development with extensive refinement of neural connections, which are highly sensitive to fetal and neonatal compromise, such as inflammatory challenges. Emerging evidence suggests that inflammatory cells in the brain such as microglia and astrocytes are pivotal in regulating synaptic structure and function. In this article, we will review the role of glia cells in synaptic physiology and pathophysiology, including microglia-mediated elimination of synapses. We propose that activation of the immune system dynamically affects synaptic organization and function in the developing brain. We will discuss the role of neuroinflammation in altered synaptic plasticity following perinatal inflammatory challenges and potential implications for neurodevelopmental and neurodegenerative disorders.
Collapse
Affiliation(s)
- Amin Mottahedin
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of GothenburgGothenburg, Sweden
| | - Maryam Ardalan
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of GothenburgGothenburg, Sweden
| | - Tetyana Chumak
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of GothenburgGothenburg, Sweden
| | - Ilse Riebe
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of GothenburgGothenburg, Sweden
| | - Joakim Ek
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of GothenburgGothenburg, Sweden
| | - Carina Mallard
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of GothenburgGothenburg, Sweden
| |
Collapse
|
|
41
|
Qanitha A, de Mol BAJM, Burgner DP, Kabo P, Pabittei DR, Yusuf I, Uiterwaal CSPM. Pregnancy-related conditions and premature coronary heart disease in adult offspring. HEART ASIA 2017; 9:90-95. [PMID: 29259659 PMCID: PMC5730950 DOI: 10.1136/heartasia-2017-010896] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 03/17/2017] [Accepted: 03/21/2017] [Indexed: 12/29/2022]
Abstract
Objective To investigate the association between complications during pregnancy and premature coronary heart disease in adult offspring. Methods We conducted a population-based case-control study of 153 Indonesian patients with a first acute coronary syndrome (ACS) (age ≤55 years) and 153 age-matched and sex-matched controls. Data on complications during pregnancy (high blood pressure, preterm delivery) and maternal infections in pregnancy were obtained, together with sociodemographic data, clinical profiles, laboratory measurements and adulthood cardiovascular disease (CVD) risk factors at hospital admission or enrolment. Conditional logistic regression was performed to assess the association between overall pregnancy complications, and specific groupings of complications and premature ACS. Results Pregnancy-related hypertension and infection were more common in mothers of cases than controls. Pregnancy complications were associated with premature offspring ACS (OR 2.9, 95% CI 1.4 to 6.0, p=0.004), and the association persisted in fully adjusted analyses (ORadjusted 4.5, 1.1 to 18.1, p=0.036). In subgroup analyses, pregnancy-related high blood pressure (ORadjusted 5.0, 1.0 to 24.7, p=0.050) and maternal infections (ORadjusted 5.2, 1.1 to 24.2, p=0.035) were associated with offspring ACS. Conclusions Offspring of mothers with complications during pregnancy have an increased risk for premature ACS in adulthood, which may be of particular relevance in populations in transition, where the incidence of both pregnancy-related morbidity and CVD are high.
Collapse
Affiliation(s)
- Andriany Qanitha
- Department of Cardio-thoracic Surgery, AMC Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Department of Physiology, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia
| | - Bastianus A J M de Mol
- Department of Cardio-thoracic Surgery, AMC Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - David P Burgner
- Murdoch Childrens Research Institute, Parkville, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.,Department of Paediatrics, Monash University, Clayton, Victoria, Australia
| | - Peter Kabo
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia
| | - Dara R Pabittei
- Department of Cardio-thoracic Surgery, AMC Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Department of Physiology, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia
| | - Irawan Yusuf
- Department of Physiology, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia
| | - Cuno S P M Uiterwaal
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| |
Collapse
|
|
42
|
Differences in 5-HT2A and mGlu2 Receptor Expression Levels and Repressive Epigenetic Modifications at the 5-HT2A Promoter Region in the Roman Low- (RLA-I) and High- (RHA-I) Avoidance Rat Strains. Mol Neurobiol 2017; 55:1998-2012. [PMID: 28265857 DOI: 10.1007/s12035-017-0457-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 02/13/2017] [Indexed: 01/12/2023]
Abstract
The serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptors regulate each other and are associated with schizophrenia. The Roman high- (RHA-I) and the Roman low- (RLA-I) avoidance rat strains present well-differentiated behavioral profiles, with the RHA-I strain emerging as a putative genetic rat model of schizophrenia-related features. The RHA-I strain shows increased 5-HT2A and decreased mGlu2 receptor binding levels in prefrontal cortex (PFC). Here, we looked for differences in gene expression and transcriptional regulation of these receptors. The striatum (STR) was included in the analysis. 5-HT2A, 5-HT1A, and mGlu2 mRNA and [3H]ketanserin binding levels were measured in brain homogenates. As expected, 5-HT2A binding was significantly increased in PFC in the RHA-I rats, while no difference in binding was observed in STR. Surprisingly, 5-HT2A gene expression was unchanged in PFC but significantly decreased in STR. mGlu2 receptor gene expression was significantly decreased in both PFC and STR. No differences were observed for the 5-HT1A receptor. Chromatin immunoprecipitation assay revealed increased trimethylation of histone 3 at lysine 27 (H3K27me3) at the promoter region of the HTR2A gene in the STR. We further looked at the Akt/GSK3 signaling pathway, a downstream point of convergence of the serotonin and glutamate system, and found increased phosphorylation levels of GSK3β at tyrosine 216 and increased β-catenin levels in the PFC of the RHA-I rats. These results reveal region-specific regulation of the 5-HT2A receptor in the RHA-I rats probably due to absence of mGlu2 receptor that may result in differential regulation of downstream pathways.
Collapse
|
|
43
|
Panaccione I, Iacovelli L, di Nuzzo L, Nardecchia F, Mauro G, Janiri D, De Blasi A, Sani G, Nicoletti F, Orlando R. Paradoxical sleep deprivation in rats causes a selective reduction in the expression of type-2 metabotropic glutamate receptors in the hippocampus. Pharmacol Res 2017; 117:46-53. [DOI: 10.1016/j.phrs.2016.11.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 11/10/2016] [Accepted: 11/22/2016] [Indexed: 12/12/2022]
|
|
44
|
Matrisciano F, Panaccione I, Grayson DR, Nicoletti F, Guidotti A. Metabotropic Glutamate 2/3 Receptors and Epigenetic Modifications in Psychotic Disorders: A Review. Curr Neuropharmacol 2016; 14:41-7. [PMID: 26813121 PMCID: PMC4787284 DOI: 10.2174/1570159x13666150713174242] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 07/03/2015] [Accepted: 07/08/2015] [Indexed: 01/08/2023] Open
Abstract
Schizophrenia and Bipolar Disorder are chronic psychiatric disorders, both considered as “major psychosis”; they are thought to share some pathogenetic factors involving a dysfunctional gene x environment interaction. Alterations in the glutamatergic transmission have been suggested to be involved in the pathogenesis of psychosis. Our group developed an epigenetic model of schizophrenia originated by Prenatal Restraint Stress (PRS) paradigm in mice. PRS mice developed some behavioral alterations observed in schizophrenic patients and classic animal models of schizophrenia, i.e. deficits in social interaction, locomotor activity and prepulse inhibition. They also showed specific changes in promoter DNA methylation activity of genes related to schizophrenia such as reelin, BDNF and GAD67, and altered expression and function of mGlu2/3 receptors in the frontal cortex. Interestingly, behavioral and molecular alterations were reversed by treatment with mGlu2/3 agonists. Based on these findings, we speculate that pharmacological modulation of these receptors could have a great impact on early phase treatment of psychosis together with the possibility to modulate specific epigenetic key protein involved in the development of psychosis. In this review, we will discuss in more details the specific features of the PRS mice as a suitable epigenetic model for
major psychosis. We will then focus on key proteins of chromatin remodeling machinery as potential target for new
pharmacological treatment through the activation of metabotropic glutamate receptors.
Collapse
Affiliation(s)
- Francesco Matrisciano
- Psychiatry and Behavioral Science, Northwestern University, Feinberg School of Medicine, 303E Chicago Ave, Chicago, IL 60611.
| | | | | | | | | |
Collapse
|
|
45
|
Santos-Toscano R, Borcel É, Ucha M, Orihuel J, Capellán R, Roura-Martínez D, Ambrosio E, Higuera-Matas A. Unaltered cocaine self-administration in the prenatal LPS rat model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2016; 69:38-48. [PMID: 27089985 DOI: 10.1016/j.pnpbp.2016.04.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 04/06/2016] [Accepted: 04/14/2016] [Indexed: 10/21/2022]
Abstract
Although cocaine abuse is up to three times more frequent among schizophrenic patients, it remains unclear why this should be the case and whether sex influences this relationship. Using a maternal immune activation model of schizophrenia, we tested whether animals at higher risk of developing a schizophrenia-like state are more prone to acquire cocaine self-administration behavior, and whether they show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction. Pregnant rats were injected with lipopolysaccharide on gestational day 15 and 16, and the offspring (both male and female) were tested in working memory (T-maze), social interaction and sensorimotor gating (prepulse inhibition of the acoustic startle response) paradigms. After performing these tests, the rats were subjected to cocaine self-administration regimes (0.5mg/kg), assessing their dose-response and extinction. Male rats born to dams administered lipopolysaccharide showed impaired working memory but no alterations to their social interactions, and both male and female rats showed prepulse inhibition deficits. Moreover, similar patterns of cocaine self-administration acquisition, responsiveness to dose shifts and extinction curves were observed in both control and experimental rats. These results suggest that the higher prevalence of cocaine abuse among schizophrenic individuals is not due to a biological vulnerability directly associated to the disease and that other factors (social, educational, economic, familial, etc.) should be considered given the multifactorial nature of this illness.
Collapse
Affiliation(s)
- Raquel Santos-Toscano
- Department of Psychobiology, School of Psychology, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Érika Borcel
- Department of Psychobiology, School of Psychology, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Marcos Ucha
- Department of Psychobiology, School of Psychology, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Javier Orihuel
- Department of Psychobiology, School of Psychology, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Roberto Capellán
- Department of Psychobiology, School of Psychology, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - David Roura-Martínez
- Department of Psychobiology, School of Psychology, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Emilio Ambrosio
- Department of Psychobiology, School of Psychology, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain.
| | - Alejandro Higuera-Matas
- Department of Psychobiology, School of Psychology, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain.
| |
Collapse
|
|
46
|
Muguruza C, Meana JJ, Callado LF. Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs. Front Pharmacol 2016; 7:130. [PMID: 27242534 PMCID: PMC4873505 DOI: 10.3389/fphar.2016.00130] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 05/05/2016] [Indexed: 11/13/2022] Open
Abstract
Schizophrenia is a chronic psychiatric disorder which substantially impairs patients' quality of life. Despite the extensive research in this field, the pathophysiology and etiology of schizophrenia remain unknown. Different neurotransmitter systems and functional networks have been found to be affected in the brain of patients with schizophrenia. In this context, postmortem brain studies as well as genetic assays have suggested alterations in Group II metabotropic glutamate receptors (mGluRs) in schizophrenia. Despite many years of drug research, several needs in the treatment of schizophrenia have not been addressed sufficiently. In fact, only 5-10% of patients with schizophrenia successfully achieve a full recovery after treatment. In recent years mGluRs have turned up as novel targets for the design of new antipsychotic medications for schizophrenia. Concretely, Group II mGluRs are of particular interest due to their regulatory role in neurotransmission modulating glutamatergic activity in brain synapses. Preclinical studies have demonstrated that orthosteric Group II mGluR agonists exhibit antipsychotic-like properties in animal models of schizophrenia. However, when these compounds have been tested in human clinical studies with schizophrenic patients results have been inconclusive. Nevertheless, it has been recently suggested that this apparent lack of efficacy in schizophrenic patients may be related to previous exposure to atypical antipsychotics. Moreover, the role of the functional heterocomplex formed by 5-HT2A and mGlu2 receptors in the clinical response to Group II mGluR agonists is currently under study.
Collapse
Affiliation(s)
- Carolina Muguruza
- Department of Pharmacology, University of the Basque Country, UPV/EHULeioa, Spain
- Centro de Investigación Biomédica en Red de Salud MentalMadrid, Spain
| | - J. Javier Meana
- Department of Pharmacology, University of the Basque Country, UPV/EHULeioa, Spain
- Centro de Investigación Biomédica en Red de Salud MentalMadrid, Spain
| | - Luis F. Callado
- Department of Pharmacology, University of the Basque Country, UPV/EHULeioa, Spain
- Centro de Investigación Biomédica en Red de Salud MentalMadrid, Spain
| |
Collapse
|
|
47
|
Ibi D, Yamada K. Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation. Int J Mol Sci 2015; 16:28218-29. [PMID: 26633355 PMCID: PMC4691039 DOI: 10.3390/ijms161226092] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 11/17/2015] [Accepted: 11/20/2015] [Indexed: 01/02/2023] Open
Abstract
Increasing epidemiological evidence indicates that perinatal infection with various viral pathogens enhances the risk for several psychiatric disorders. The pathophysiological significance of astrocyte interactions with neurons and/or gut microbiomes has been reported in neurodevelopmental disorders triggered by pre- and postnatal immune insults. Recent studies with the maternal immune activation or neonatal polyriboinosinic polyribocytidylic acid models of neurodevelopmental disorders have identified various candidate molecules that could be responsible for brain dysfunction. Here, we review the functions of several candidate molecules in neurodevelopment and brain function and discuss their potential as therapeutic targets for psychiatric disorders.
Collapse
Affiliation(s)
- Daisuke Ibi
- Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan.
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
| | - Kiyofumi Yamada
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
| |
Collapse
|
|
48
|
Maternal lipopolysaccharide treatment differentially affects 5-HT2A and mGlu2/3 receptor function in the adult male and female rat offspring. Neuropharmacology 2015; 97:275-88. [DOI: 10.1016/j.neuropharm.2015.05.029] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 05/08/2015] [Accepted: 05/22/2015] [Indexed: 12/17/2022]
|
|
49
|
Converging models of schizophrenia--Network alterations of prefrontal cortex underlying cognitive impairments. Prog Neurobiol 2015; 134:178-201. [PMID: 26408506 DOI: 10.1016/j.pneurobio.2015.09.010] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 09/10/2015] [Accepted: 09/17/2015] [Indexed: 02/08/2023]
Abstract
The prefrontal cortex (PFC) and its connections with other brain areas are crucial for cognitive function. Cognitive impairments are one of the core symptoms associated with schizophrenia, and manifest even before the onset of the disorder. Altered neural networks involving PFC contribute to cognitive impairments in schizophrenia. Both genetic and environmental risk factors affect the development of the local circuitry within PFC as well as development of broader brain networks, and make the system vulnerable to further insults during adolescence, leading to the onset of the disorder in young adulthood. Since spared cognitive functions correlate with functional outcome and prognosis, a better understanding of the mechanisms underlying cognitive impairments will have important implications for novel therapeutics for schizophrenia focusing on cognitive functions. Multidisciplinary approaches, from basic neuroscience to clinical studies, are required to link molecules, circuitry, networks, and behavioral phenotypes. Close interactions among such fields by sharing a common language on connectomes, behavioral readouts, and other concepts are crucial for this goal.
Collapse
|
|
50
|
In the grey zone between epilepsy and schizophrenia: alterations in group II metabotropic glutamate receptors. Acta Neurol Belg 2015; 115:221-32. [PMID: 25539775 DOI: 10.1007/s13760-014-0407-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 12/05/2014] [Indexed: 01/09/2023]
Abstract
Glutamate is the major excitatory neurotransmitter in the brain. The glutamate system plays an important role in the formation of synapses during brain development and synaptic plasticity. Dysfunctions in glutamate regulation may lead to hyperexcitatory neuronal networks and neurotoxicity. Glutamate excess is possibly of great importance in the pathophysiology of several neurological and psychiatric disorders such as epilepsy and schizophrenia. Interestingly, cross talk between these disorders has been well documented: psychiatric comorbidities are frequent in epilepsy and temporal lobe epilepsy is one of the highest risk factors for developing psychosis. Therefore, dysfunctions in glutamatergic neurotransmission might constitute a common pathological mechanism. A major negative feedback system is regulated by the presynaptic group II metabotropic glutamate (mGlu) receptors including mGlu2/3 receptors. These receptors are predominantly localised extrasynaptically in basal ganglia and limbic structures. Hence, mGlu2/3 receptors are an interesting target for the treatment of disorders like epilepsy and schizophrenia. A dysfunction in the glutamate system may be associated with alterations in mGlu2/3 receptor expression. In this review, we describe the localization of mGlu2/3 receptors in the healthy brain of mice, rats and humans. Secondly, changes in mGlu2/3 receptor density of the brain regions affected in epilepsy and schizophrenia are summarised. Increased mGlu2/3 receptor density might represent a compensatory mechanism of the brain to regulate elevated glutamate levels, while reduced mGlu2/3 receptor density in some brain regions may further contribute to the aberrant hyperexcitability. Further research considering the mGlu2/3 receptor can contribute significantly to the understanding of the etiological and therapeutic role of group II mGlu receptor in epilepsy, epilepsy with psychosis and schizophrenia.
Collapse
|