Somatosensory cortical development and plasticity

描述(由申请人提供)：这项提案侧重于NMDAR功能遗传受损小鼠的躯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形图中的地形图连接和图形发展的一个很好的模型系统。缺乏NMDAR关键亚单位的小鼠脑干中的躯体感觉模式被取消。表达较低水平NMDAR功能的小鼠也显示出在整个躯体感觉通路上都没有模式。兴奋性神经元中NMDAR的皮质受限干扰的小鼠也在躯体感觉身体地图区域的皮质图案方面显示出严重的缺陷。因此，体感区域特异性基因敲除小鼠模型提供了一个很好的手段来剖析NMDAR及其下游信号分子在突触前和突触后神经元件模式中的作用。这项提议的长期目标是揭示NMDAR功能受损后，躯体感觉突触电路是如何改变的。在体内和体外的电生理方法将被用来阐明这些小鼠躯体感觉皮质和丘脑的功能变化。这些研究将补充正在进行的形态分析，并全面揭示NMDAR在躯体感觉神经映射的组织和模式中的作用。 公共卫生相关性：NMDAR(NMDAR)在大脑发育、学习和记忆、发育性神经障碍、成瘾、痛觉和兴奋性毒性中发挥重要作用。在这项建议中，我们将通过检测NMDAR在小鼠模型中特定区域遗传失效的生理缺陷来测试NMDAR在躯体感觉神经回路正常发育中的作用。了解NMDAR功能在正常脑发育中的基本细胞和分子机制对于关键的发育性大脑疾病的评估和制定治疗策略是至关重要的。

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.