Functional State of Developing Retinogeniculate Synapse

描述（由申请人提供）：我们目前对感觉连接的活动依赖性细化的许多理解是基于在发育中的视网膜神经通路中所做的工作。尽管有压倒性的证据强调活动在塑造retinogeniculate连接的完善中的作用，这些过程背后的细胞和分子机制仍然是一个激烈的调查主题。我们已经开发了一个啮齿动物模型的视觉系统的发展，我们的特点是在出生后早期的结构和功能的变化发生在外侧膝状体核（LGN）。我们的实验表明，在retinogeniculate轴突图案和连接的变化与赫布样修改突触强度和L-型钙离子通道的激活。然而，L型钙通道的作用及其在retinogeniculate发展过程中的表达仍然在很大程度上未被探索。该项目的主要目标是研究出生后早期L型钙离子活性的性质，并建立这种活性与视网膜神经连接重塑之间的直接联系。我们将使用电生理学，解剖学和生物化学技术来描绘L-型钙通道表达的性质及其在retinogeniculate发育中的作用。我们将利用转基因小鼠系，其中通过靶向缺失Ca 2+通道的β 2或β 3亚基，L型Ca 2+活性和通道表达已严重减弱。这些小鼠提供了一个独特的机会，将L-型Ca 2+功能与LGN中的突触稳定和活动依赖性重塑联系起来。

DESCRIPTION (provided by applicant): Much of our present understanding regarding the activity-dependent refinement of sensory connections is based on work done in the developing retinogeniculate pathway. Despite the overwhelming evidence underscoring the role of activity in shaping the refinement of retinogeniculate connections, the cellular and molecular mechanisms underlying these processes remain a topic of intense inquiry. We have developed a rodent model of visual system development in which we characterized the structural and functional changes occurring in the lateral geniculate nucleus (LGN) during early postnatal life. Our experiments reveal that the changes in retinogeniculate axon patterning and connectivity are linked to Hebbian-like modifications in synaptic strength and the activation of L-type Ca2+ channels. However, the role of L-type Ca2+ channels and their expression during retinogeniculate development remain largely unexplored. The major goals of this project is to investigate the nature of L-type Ca2+ activity during early postnatal life and establish a direct link between such activity and the remodeling of retinogeniculate connections. We shall use electrophysiological, anatomical, and biochemical techniques to delineate the nature of L-type Ca2+ channel expression and its role in retinogeniculate development. We shall take advantage of transgenic mice lines in which L-type Ca2+ activity and channel expression has been severely attenuated by the targeted deletion of either the beta2 or beta3 subunit of the Ca2+ channel. These mice offer a unique opportunity to relate L-type Ca2+ function with synapse stabilization and activity dependent remodeling in LGN.