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Mechanisms and pathogenic role of early corticostriatal dysfunction in Shank3B-/- mice

Shank3B-/-小鼠早期皮质纹状体功能障碍的机制及致病作用

基本信息

批准号：
10308443
负责人：
Rui Peixoto
金额：
$ 39.39万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10308443
关键词：
Address Adult Affect Animals Behavior Behavioral Biological Models Brain Cells Cognitive deficits Corpus striatum structure Cre driver Cyclic AMP-Dependent Protein Kinases Defect Development Disease Environment Exhibits Functional disorder Genetic Genetic study Glutamates Goals Growth Hyperactivity Hypertrophy Impairment Intervention Knowledge Label Laboratories Light Mind Molecular Mus Mutation Neurodevelopmental Disorder Neurons Pathogenesis Pathogenicity Pathway interactions Pattern Peptides Phenotype Population Prefrontal Cortex Process Protein Inhibition Protein Kinase A Inhibitor Reporter Reporting Risk Role Social Interaction Testing Therapeutic Time Transgenic Mice Transgenic Organisms Viral Wild Type Mouse Work autism spectrum disorder autistic imaging study individuals with autism spectrum disorder insight loss of function maladaptive behavior motor deficit nerve supply optogenetics postnatal postnatal development postnatal period protein expression relating to nervous system repetitive behavior response risk variant social deficits synaptogenesis targeted treatment

项目摘要

PROJECT SUMMARY Despite increasing knowledge of the genetic underpinnings of autism risk, the specific pathogenic mechanisms underlying the emergence of motor and cognitive deficits in autism spectrum disorders (ASD) remain unclear. Recent imaging and genetic studies have pointed to corticostriatal dysfunction has a prevalent pathophysiology in ASD. In particular, hypertrophy and abnormal functional connectivity of prefrontal cortex (PFC) and dorsomedial striatum (DMS) have been reported in multiple autistic individuals, providing a potential neuropathological substrate for the repetitive behaviors and social deficits associated with autism. Our laboratory has shown that mice with loss of function deletions in SHANK3 (Shank3B-/-), a highly penetrant monogenic cause of autism, exhibit hyperactivity and abnormal patterns of connectivity in corticostriatal circuits during postnatal development. Behavioral deficits in these animals also emerge during these early developmental periods, suggesting that early corticostriatal dysfunction might be an important pathogenic mechanism in SHANK3 associated disorders. Here we propose to further characterize how striatal circuit development is impaired by loss of Shank3 and identify the specific corticostriatal pathways affected in these conditions (Aim1). In addition, using recently developed conditional transgenic mice that allow cell-specific manipulation of Shank3 expression we will dissect the specific mechanisms leading to corticostriatal connectivity abnormalities (Aim 2). In addition, using new molecular strategies that normalize early excitatory drive in striatal neurons, we will determine the pathogenic role of early striatal circuit dysfunction in the emergence of maladaptive behaviors in Shank3B-/- mice (Aim 3). This work will advance our understanding of the basic mechanisms and developmental rules regulating the maturation of corticostriatal circuits and provide important insights into the pathogenesis of ASD and other neurodevelopmental disorders with early activity imbalances in corticostriatal circuits.

项目总结