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Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism.

ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder, featuring social communication deficit and repetitive/restricted behaviors as common symptoms. Its prevalence has continuously increased, but, till now, there are no therapeutic approaches to relieve the core symptoms, particularly social deficit. In previous studies, abnormal function of the glutamatergic neural system has been proposed as a critical mediator and therapeutic target of ASD-associated symptoms. Here, we investigated the possible roles of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in autism symptoms using two well-known autistic animal models, Cntnap2 knockout (KO) mice and in utero valproic acid-exposed ICR (VPA) mice. We found that Cntnap2 KO mice displayed decreased glutamate receptor expression and transmission. Contrarily, VPA mice exhibited increased glutamate receptor expression and transmission. Next, we investigated whether AMPAR modulators (positive-allosteric-modulator for Cntnap2 KO mice and antagonist for VPA mice) can improve autistic symptoms by normalizing the aberrant excitatory transmission in the respective animal models. Interestingly, the AMPAR modulation specifically ameliorated social deficits in both animal models. These results indicated that AMPAR-derived excitatory neural transmission changes can affect normal social behavior. To validate this, we injected an AMPAR agonist or antagonist in control ICR mice and, interestingly, these treatments impaired only the social behavior, without affecting the repetitive and hyperactive behaviors. Collectively, these results provide insight into the role of AMPARs in the underlying pathophysiological mechanisms of ASD, and demonstrate that modulation of AMPAR can be a potential target for the treatment of social behavior deficits associated with ASD.

SUBMITTER: Kim JW

PROVIDER: S-EPMC6300529 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism.

Kim Ji-Woon JW Park Kwanghoon K Kang Ri Jin RJ Gonzales Edson Luck T ELT Kim Do Gyeong DG Oh Hyun Ah HA Seung Hana H Ko Mee Jung MJ Kwon Kyoung Ja KJ Kim Ki Chan KC Lee Sung Hoon SH Chung ChiHye C Shin Chan Young CY

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20180522 2

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, featuring social communication deficit and repetitive/restricted behaviors as common symptoms. Its prevalence has continuously increased, but, till now, there are no therapeutic approaches to relieve the core symptoms, particularly social deficit. In previous studies, abnormal function of the glutamatergic neural system has been proposed as a critical mediator and therapeutic target of ASD-associated symptoms. Here, we investigated ...[more]

PMID: 29899405

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Project description:Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

Dataset Information

Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism.

Publications

Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism.

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