Thalamocortical circuit defects in developmental brain disorders

 描述（由申请人提供）：越来越多的证据表明，兴奋性和抑制性神经传递中断是自闭症谱系障碍（ASD）和Rett综合征（RTT）的病因。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）在发育中的大脑中表达。编码MET受体酪氨酸激酶的人类基因MET已被鉴定为ASD的突出危险因素。RTT是由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理解各种脑区的形态和生理变化提供了宝贵的机会，并且它们允许开发治疗策略。ASD和RTT影响的儿童表现出不同的躯体感觉行为倾向，这表明在躯体感觉信息处理的具体缺陷。我们专注于体感丘脑皮层电路生理学和体内功能分析的发展，使用特定区域的遗传功能丧失小鼠模型，以揭示基本的科学机制，丘脑皮层电路缺陷的遗传破坏后，这两个基因与ASD和RTT。我们在MeCP 2缺乏的鸟鼠模型中的初步结果表明，桶皮质第4层兴奋性神经元的兴奋和抑制平衡偏向于抑制。相反，当Met信号在皮质兴奋性神经元中被破坏时，杂合小鼠显示抑制丧失。我们专注于小鼠的初级躯体感觉（须“桶”）皮层，因为它的模式化组织和良好的特点发展和可塑性。我们将联合收割机小鼠遗传学与电生理学、功能成像、生物化学和行为分析相结合，以了解这些特定遗传中断后丘脑皮质电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.