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Identifying Convergent Circuit Disruptions Across Genetically-Distinct Models of Autism

识别基因不同的自闭症模型中的收敛回路中断

基本信息

批准号：
10638144
负责人：
Benjamin D Auerbach
金额：
$ 42.49万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638144
关键词：
Address Affect Animals Antibiotics Auditory Auditory Perception Auditory Perceptual Disorders Auditory area Auditory system Behavior Behavioral Behavioral Symptoms Biological Assay Biological Models Brain Clinical Clinical Trials Complex DNA Sequence Alteration Development Disease Disease model Electrophysiology (science)Equilibrium Exhibits Extracellular Matrix Proteins FDA approved FMR1 FRAP1 gene Foundations Fragile X Syndrome Functional disorder Genetic Hippocampus Human Genetics Hypersensitivity Impairment Interneuron function Interneurons Intervention Knockout Mice Label Lead Link Maps Memory Metabolic Minocycline Modeling Molecular Molecular Profiling Mus Mutation Nature Neuroanatomy Neurocognitive Neuronal Dysfunction Neurons Parvalbumins Pathogenesis Pathway interactions Phenotype Physiological Protein Biosynthesis Rattus Recurrence Research Risk Factors Rodent Model Sclerosis Sensory Signal Transduction Social Behavior Symptoms Synapses Techniques Testing Training Tuberous Sclerosis auditory processing autism spectrum disorder behavioral phenotyping cell type communication behavior density in vivo information processing innovation lens mouse model mutant neural circuit neurophysiology neuropsychiatry next generation novel novel therapeutics optogenetics pharmacologic prevent programs sensory system skills sound synaptic inhibition tool treatment strategy

项目摘要

Identifying Convergent Circuit Disruptions Across Genetically-Distinct Rat Models of ASD Summary: Recent advances from human genetic and animal studies have greatly increased our understanding of the molecular and cellular basis of autism spectrum disorders (ASD). Connecting these risk factors to clinical symptoms in autism remains a significant challenge that has impeded the development of ASD therapies, as evidenced by disappointing results from recent large-scale clinical trials. A fundamental question is if distinct ASD mutations converge on shared disease mechanisms at some level of neuronal function to ultimately give rise to the behavioral and neurocognitive phenotypes that define autism. Identifying these pathophysiological convergence points is essential for developing treatment strategies that may generalize across genetically heterogenous forms of ASD. We have previously shown that rodent models of the two most common genetically-defined causes of autism— Fmr1 KO mouse model of Fragile X syndrome (FX) and Tsc2+/- mouse model of tuber sclerosis complex (TSC)— exhibit opposite synaptic and cellular phenotypes that responded to opposite pharmacological interventions, despite sharing a molecular pathway and presenting with similar behavioral phenotypes. This proposal will determine if Fmr1 and Tsc2 mutations converge on common circuit disruptions that can account for shared behavioral phenotypes in these disorders. We will address this question through the lens of the auditory system, as auditory processing impairments are a common and debilitating sensory phenotype in ASD that directly impacts communicative and social behavior while also providing robust and translationally-relevant behavioral and physiological read-outs, due to its well- characterized neuroanatomy and evolutionary conserved nature. Specifically, this proposal will test the hypothesis that circuit hyperexcitability due to altered excitatory/inhibitory synaptic balance and dysregulated parvalbumin expressing (PV+) interneuron function is a convergent disease mechanism that leads to shared deficits in auditory perception and information processing in rat models of FX and TSC. This will be accomplished by combining the unique behavioral advantaged of rat models with in vivo and ex vivo electrophysiological recordings, cell-type specific optogenetic manipulations, and molecular profiling techniques. Determining how Fmr1 and Tsc2 mutations lead to auditory processing deficits and neural circuit dysfunction will not only help identify novel therapies for disabling sensory phenotypes in these disorders, but may shed light on recurring pathophysiological motifs that generalize across neurocognitive domains and extend to diverse forms of ASD.

在遗传上不同的ASD大鼠模型中识别收敛电路中断