Signaling cascades in sensory map development

描述(申请人提供)：在皮质感觉图中，丘脑皮质传入(TCA)以有组织的阵列将外围感觉传输到不同的皮质神经元模块中，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”，暴露在异常的感觉体验中，每个人身上形成的这些皮层图谱都可能被改变。早期生命中神经元电路的错误连接可能是导致神经疾病的主要原因，包括自闭症、精神分裂症和先天性癫痫。以小鼠胡须MAP为模型系统，我们发现代谢性谷氨酸受体5(MGluR5)信号参与了解剖结构的塑造和丘脑皮质连接的突触功能和可塑性的调节。消除皮层主神经元的mGluR5功能导致病变诱导的TCA重排的临界期延长。内源性大麻素(ECB)是已知的调节突触传递的逆行信使，在许多神经元中被mGluR5激活而合成。我们推测，在皮质MAP的发育过程中，皮质神经元中的mGluR5信号指示TCA的解剖修饰，ECB至少部分地介导了丘脑皮质突触的神经活性依赖的重构。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如何影响大脑皮层回路和网络活动的功能发育？内源性大麻素是否介导mGluR5对皮层环路发育的影响？将结合遗传学、解剖学、电生理学和药理学方法来实现这些目标。这项研究将提供对mGluR5和ECbs信号在神经回路发育中的确切理解。MGluR5和ECB都是人类治疗干预的潜在药物靶点。对它们在神经发育过程中作用的详细了解不仅对于了解正常的大脑功能至关重要，而且对于合理评估可能影响发育中的胎儿的治疗或药物暴露(例如大麻)也具有重要意义。

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.