Signaling cascades in sensory map development

描述（由申请人提供）：在皮层感觉图中，丘脑皮层传入（TCA）以有组织的阵列将外周感觉传输到不同的皮层神经元模块中，以提供外部感觉世界的地形图表示。在出生后发育的“关键时期”，这些在每个个体中形成的皮层地图都可以通过暴露于异常的感觉体验而改变。在生命早期，神经元回路的错误接线可能是神经系统疾病的主要原因，包括自闭症，精神分裂症和先天性癫痫。以小鼠须状图为模型系统，我们发现代谢型谷氨酸受体5（mGluR5）信号参与了丘脑皮质连接的解剖结构的塑造和突触功能的调节。消除皮质主神经元中的mGluR5功能导致病变诱导的TCA重排的关键期延长。内源性大麻素（eCB）是调节突触传递的已知逆行信使，在许多神经元中在mGluR5激活后合成。我们假设，在皮层地图的发展mGluR5信号在皮层神经元指示的解剖修改的TCAs和eCB介导，至少部分，丘脑皮质突触的神经活性依赖性重塑。在拟议的工作中，我们将解决三个具体目标：mGluR5如何影响桶皮质的发展和可塑性？mGluR5如何影响皮层回路和网络活动的功能发育？内源性大麻素介导mGluR5对发育中的皮层回路的影响吗？将采用遗传学、解剖学、电生理学和药理学方法的组合来实现这些目标。这项研究将提供一个坚实的理解mGluR5和eCBs信号在开发神经回路。mGluR5和eCB都是人类治疗干预的潜在药物靶点。详细了解它们在神经发育过程中的作用不仅对于理解正常的脑功能至关重要，而且对于合理评估治疗或药物暴露（例如，大麻），可能会影响发育中的胎儿。

DESCRIPTION (provided by applicant): In cortical sensory maps, thalamocortical afferents (TCAs) transmit peripheral sensations in organized arrays into distinct cortical neuronal modules to provide a topographic representation of the external sensory world. These cortical maps that form in every individual can be altered by exposure to abnormal sensory experience during a "critical period" of postnatal development. Mis-wiring of neuronal circuits during early life is likely to be a major cause of neurological disorders, including autism, schizophrenia, and congenital epilepsy. Using mouse whisker-maps as a model system, we found that metabotropic glutamate receptor 5 (mGluR5) signaling is involved in sculpting the anatomical structures and in regulating synaptic function and plasticity of thalamocortical connections. Eliminating mGluR5 function in cortical principal neurons resulted in a prolonged critical period for lesion-induced rearrangements of TCAs. Endocannabinoids (eCBs), known retrograde messengers in regulating synaptic transmission, are synthesized upon mGluR5 activation in many neurons. We hypothesize that during cortical map development mGluR5 signaling in cortical neurons instructs the anatomical modification of TCAs and that eCBs mediate, at least in part, the neural-activity dependent remodeling of thalamocortical synapses. In the proposed work we will address three specific aims: How does mGluR5 affect the development and plasticity of barrel cortex? How does mGluR5 affect functional development of cortical circuits and network activity? Do endocannabinoids mediate mGluR5 influences on developing cortical circuits? A combination of genetic, anatomical, electrophysiological, and pharmacological approaches will be employed to accomplish these aims. This study will provide a firm understanding of mGluR5 and eCBs signaling in developing neural circuits. Both mGluR5 and eCBs are potential drug targets for therapeutic interventions in humans. A detailed knowledge of their roles during neural development is critical not only for understanding normal brain function, but also to provide significant insights for the rational assessment of therapies or drug exposure (e.g., cannabis) that might affect the developing fetus.