Thalamocortical circuit defects in developmental brain disorders

 描述(申请人提供)：越来越多的证据表明，在自闭症谱系障碍(ASD)和Rett综合征(RTT)的病因中，兴奋性和抑制性神经传递中断。特定的遗传效应与这些发育障碍有关。MET受体及其配体肝细胞生长因子(HGF)及其受体在发育中的脑中均有表达。编码MET受体酪氨酸激酶的人类基因MET已被确认为ASD的显著危险因素。RTT是一种由MECP2基因突变引起的神经发育障碍。MET和MeCP2功能丧失小鼠模型为了解不同脑区的形态和生理变化提供了宝贵的机会，并为开发治疗策略提供了宝贵的机会。受ASD和RTT影响的儿童都表现出不同的躯体感觉行为倾向，提示在躯体感觉信息处理方面存在特定缺陷。我们专注于躯体感觉丘脑皮质回路生理学和体内发育中的功能分析，使用区域特定的遗传功能丧失小鼠模型来揭示与ASD和RTT相关的这两个基因遗传中断后丘脑皮质回路缺陷的基本科学机制。我们在MeCP2缺乏的Bird小鼠模型上的初步结果表明，桶状皮质第四层兴奋性神经元的兴奋和抑制的平衡倾向于抑制。相反，当皮质兴奋性神经元中的Met信号被扰乱时，杂合子小鼠表现出抑制作用的丧失。我们将重点放在小鼠初级体感(胡须“桶”)皮质，因为它的模式组织和良好的发育和可塑性特征。我们将小鼠遗传学与电生理、功能成像、生化和行为分析相结合，以了解这些特定基因中断后丘脑皮质回路缺陷的细胞机制和后果。

 DESCRIPTION (provided by applicant): There is increasing evidence, implicating disruption of excitatory and inhibitory neurotransmission in the etiology of Autism Spectrum Disorders (ASD) and Rett Syndrome (RTT). Specific genetic effects are associated with these developmental disorders. MET receptor and it ligand hepatocyte growth factor (HGF) and both are expressed in the developing brain. The human gene MET, which encodes MET receptor tyrosine kinase has been identified as a prominent risk factor for ASD. RTT is a neurodevelopmental disorder caused by mutations in the MECP2 gene. Met and Mecp2 loss-of-function mouse models provide invaluable opportunities in understanding morphological and physiological changes in various brain regions, and they allow for development of therapeutic strategies. Both ASD and RTT affected children display distinct somatosensory behavioral proclivities suggesting specific defects in somatosensory information processing. We focus on the somatosensory thalamocortical circuit physiology and in vivo functional analyses in development, using region-specific genetic loss of function mouse models to uncover basic scientific mechanisms of thalamocortical circuitry defects following genetic disruption of these two genes associated with ASD and RTT. Our preliminary results in the Bird mouse model of MeCP2 deficiency indicate that the balance of excitation and inhibition in Layer 4 excitatory neurons of barrel cortex is biased toward inhibition. In contrast when Met signaling is disrupted in cortical excitatory neurons, heterozygous mice show loss of inhibition. We focus on the mouse primary somatosensory (whisker "barrel") cortex because of its patterned organization and well-characterized development and plasticity. We combine mouse genetics with electrophysiological, functional imaging, biochemical, and behavioral analyses to understand the cellular mechanisms and consequences of thalamocortical circuitry defects following these specific genetic disruptions.