Somatosensory cortical development and plasticity

描述（由申请人提供）：本提案侧重于NMDAR功能基因受损小鼠体感觉丘脑皮质回路的发展。啮齿动物体感通路是研究体感地图中地形连接和模式发展的一个很好的模型系统。缺乏NMDARs关键亚基的小鼠脑干中的体感觉模式被废除。表达较低水平NMDAR功能的小鼠也表现出沿体感觉通路的模式缺失。兴奋性神经元中NMDARs皮层限制性破坏的小鼠在体感觉体图区域内也表现出严重的皮质模式缺陷。因此，体感觉区域特异性敲除小鼠模型提供了一种很好的方法来剖析NMDARs和下游信号分子在突触前和突触后神经元件的模式化中的作用。本研究的长期目标是揭示NMDAR功能受损后体感觉突触回路的改变。体内和体外电生理方法将用于阐明这些小鼠体感觉皮层和丘脑的功能变化。这些研究将补充正在进行的形态学分析，并全面揭示NMDARs在体感觉神经图谱的组织和模式中的作用。

DESCRIPTION (provided by applicant): This proposal focuses on the development of somatosensory thalamocortical circuitry in mice with genetically impaired NMDAR function. Rodent somatosensory pathway is an excellent model system to study development of topographic connections and patterning within somatosensory maps. Somatosensory patterns are abolished in the brainstem of mice lacking the critical subunit of the NMDARs. Mice that express lower levels of NMDAR function also show absence of patterning all along the somatosensory pathway. Mice with cortex-restricted disruption of NMDARs in excitatory neurons also display severe defects in cortical patterning within the somatosensory body map region. Thus, somatosensory region-specific knockout mouse models provide an excellent means to dissect out the role of NMDARs and downstream signaling molecules in patterning of pre- and postsynaptic neural elements. The long-term objective of this proposal is to reveal how somatosensory synaptic circuitry is altered following impaired NMDAR function. In vivo and in vitro electrophysiological approaches will be used to elucidate functional changes in the somatosensory cortex and thalamus of these mice. These studies will complement ongoing morphological analyses and overall reveal the role of NMDARs in organization and patterning of somatosensory neural maps. PUBLIC HEALTH RELEVANCE: NMDA receptors (NMDARs) play a major role in brain development, learning and memory, developmental neurological disorders, addiction, pain perception and in excitotoxicity. In this proposal we shall test the role of NMDARs in normal development of somatosensory neural circuits by examining physiological defects in region-specific genetic invalidation of NMDARs in mouse models. Understanding basic cellular and molecular mechanisms of NMDAR function in normal brain development is crucial for critical evaluation of developmental brain disorders and in developing therapeutic strategies.