Signaling Cascades in Sensory Map Development

描述（由申请人提供）：在皮层感觉图中，丘脑皮层传入事件（TCAs）将周围感觉以有组织的阵列传递到不同的皮层神经元模块，以提供外部感觉世界的地形表征。在出生后发育的“关键时期”，暴露在异常的感官体验中，每个个体形成的这些皮层地图都可能被改变。在生命早期，神经回路的错误连接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。利用小鼠须状图作为模型系统，我们发现代谢性谷氨酸受体5 （mGluR5）信号通路参与了丘脑皮质连接的解剖结构塑造、突触功能调节和可塑性调节。消除皮质主神经元中mGluR5的功能导致损伤诱导的TCAs重排的临界期延长。内源性大麻素（eCBs）是调节突触传递的逆行信使，在许多神经元中是通过mGluR5激活合成的。我们假设，在皮质图发育过程中，皮质神经元中的mGluR5信号指示TCAs的解剖修饰，而eCBs至少部分地介导了丘脑皮质突触的神经活动依赖性重构。在拟议的工作中，我们将解决三个具体目标：mGluR5如何影响桶状皮质的发育和可塑性？mGluR5如何影响皮质回路和网络活动的功能发育？内源性大麻素介导mGluR5对皮质回路发育的影响吗？遗传学、解剖学、电生理学和药理学方法的结合将被用来实现这些目标。这项研究将为mGluR5和eCBs信号在神经回路发育中的作用提供一个明确的认识。mGluR5和eCBs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理解正常的大脑功能至关重要，而且对合理评估可能影响胎儿发育的治疗或药物暴露（如大麻）提供重要见解。

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.