Functional state of developing retinogeniculate synapse

描述(申请人提供)：我们开发了一个视觉系统发育的小鼠模型，该模型描述了视网膜神经节细胞轴突与它们在丘脑外侧膝状体核(LGN)的突触后目标之间发生的结构和功能变化。虽然已经描述了视网膜起源轴突模式和连通性的许多变化，但仍有许多问题尚未解决。例如，我们对神经元素和细胞内信号级联知之甚少，它们决定了为什么某些视网膜输入被保留和加强，而另一些输入被削弱并最终被消除。虽然许多诱导的连接性改变依赖于自发的视网膜活动和Hebbian形式的突触可塑性，但视觉诱发活动和突触可塑性与维持新重建的连接相关的作用尚未得到充分探讨。为了充分了解视网膜连接重塑是如何发生的，还需要关于视网膜原性突触和LGN中继细胞树突的生长和成熟的详细形态信息。本次更新的主要目标是：利用电生理学、解剖学和生化技术详细了解L型钙通道活动的性质，这一事件似乎对于调节LGN的活动依赖可塑性至关重要；建立L型活动与视网膜原基连接重塑之间的联系；探索视觉诱发活动的变化如何影响新重塑的视黄素原连接的维持；以及检查发育中的LGN细胞的树突形态，并确定其结构与功能的关系如何与视网膜轴突重塑相协调。研究是在野生型色素沉着的小鼠身上进行的，以及那些L型钙通道的表达和活性因23亚基的靶向缺失而严重减弱的小鼠。小鼠发育中的视黄素生成途径已成为研究突触连接重塑机制的一个强大的模型系统。因此，这些研究将提供关于发育中的大脑如何形成准确的连接模式的有价值的信息，并为研究和治疗由异常连接模式形成的发育和神经疾病提供进一步的洞察力。公共卫生相关性：这些研究将提供关于发育中的大脑如何形成准确的连接模式的有价值的信息，并为研究和治疗由异常连接模式形成的发育和神经疾病提供进一步的见解。

Description (provided by applicant): We have developed a mouse model of visual system development which characterizes the structural and functional changes occurring between retinal ganglion cell axons and their postsynaptic targets in the lateral geniculate nucleus (LGN) of thalamus. While many of the changes in retinogeniculate axon patterning and connectivity have been described, a number of issues remain unresolved. For example we know little about the neural elements and intracellular signaling cascades that govern why certain retinal inputs are preserved and strengthened while others are weakened and eventually eliminated. While many of the inductive changes in connectivity rely on a spontaneous retinal activity and a Hebbian form of synaptic plasticity, the role of visually evoked activity and the synaptic plasticity associated with the maintenance of newly remodeled connections has not been fully explored. Detailed morphological information about the growth and maturation of retinogeniculate synapses and the dendrites of LGN relay cells is also needed to fully appreciate how the remodeling of retinal connections occurs. The major goals of this renewal are: to use electrophysiological, anatomical, and biochemical techniques to detail the nature of L-type Ca2+ channel activity an event that appears essential for mediating activity dependent plasticity in LGN; to establish a link between L-type activity and the remodeling of retinogeniculate connections; to explore how alterations in visually evoked activity affect the maintenance of newly remodeled retinogeniculate connections; and to examine the dendritic morphology of developing LGN cells and determine how their structure-function relations are coordinated with the remodeling of retinal axons. Studies are done in wild-type pigmented mice as well as those in which L-type Ca2+ channel expression and activity has been severely attenuated by the targeted deletion of the 23 subunit. The developing retinogeniculate pathway in the mouse has emerged as a powerful model system to study the mechanisms underlying the remodeling of synaptic connections. Therefore, these studies will provide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity. PUBLIC HEALTH RELEVANCE: These studies will provide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity.