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A Circuit Mechanism for the Development of Cortico-cortical Connectivity

皮质-皮质连接发展的电路机制

基本信息

批准号：
10267037
负责人：
Natalia Vanesa De Marco Garcia
金额：
$ 51.1万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2020-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10267037
关键词：
ASD patient Ablation Adolescent Adult Affect Anatomy Angelman Syndrome Area Behavior Behavioral Brain Brain region Calcium Cerebral cortex Child Cognitive Contralateral Defect Development Developmental Process Disease Distant Emergency Situation Environmental Risk Factor Equilibrium Etiology Functional disorder Genes Genetic Genetic Predisposition to Disease Goals Head Image Impairment Interneurons Ipsilateral Knowledge Lead Motor Cortex Mus Mutation Neonatal Neurons Outcome Parietal Lobe Pathway interactions Patients Pattern Perception Phenotype Process Pyramidal Cells Research Role Schizophrenia Sensory Signal Pathway Signal Transduction Somatosensory Cortex Source Stimulus Study models Techniques Testing Vibrissae Virus Work autism spectrum disorder barrel cortex brain abnormalities childhood epilepsy critical period experimental study gamma-Aminobutyric Acid high risk in vivo innovation mutant neonate neuronal circuitry neuropathology pup rabies viral tracing receptor translational impact two-photon

项目摘要

Project Summary In the cerebral cortex, gamma-aminobutyric acid (GABA)ergic interneurons are the major source of inhibition. Interneuron dysfunction is strongly associated with autism and childhood epilepsy. We demonstrated that environmental influences such as electrical activity are fundamental for the maturation of GABAergic circuits. However, the identity of the activity patterns controlling interneuron development remains poorly understood. The long-term goal of this research is to uncover how early interneuron dysfunction leads to lasting neuropathologies. The objective of this proposal is to reveal the signaling pathways underlying activity- dependent development and to assess how perturbations in this process lead to aberrant brain function. To this end, we will use the murine barrel cortex as a well-established model for the study of activity-dependent circuit maturation. We will focus our studies in superficial circuits since our previous work indicates that these circuits are exquisitely sensitive to environmental perturbations in the neonate. In the near term, this proposal is aimed at investigating the role of specific interneuron subtypes in regulating the emergence of long range connectivity (Aim 1). In addition, this project will determine the role of GABAergic inputs for the functional maturation of pyramidal networks. We will study the role of Gabrb3, a gene encoding for the beta3 subunit of GABAA channel. Mutations in this gene are strongly associated with Angelman syndrome and ASD (Aim 2). Finally, we will assess how developmental defects in early GABAergic signaling lead to abnormal brain activity in cortico-cortical pathways during development (Aim 3). With respect to the outcomes, our work is expected to identify basic mechanisms fundamental for the emergency of a healthy E/I balance. In addition, these results are expected to have a significant translational impact because they will expand our mechanistic knowledge on how mutations in the GABRB3 gene may lead to behavioral abnormalities frequently observed in ASD patients.

项目总结