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的精细化的大部分理解是基于在发育中的视黄醇生成途径中所做的工作。尽管有压倒性的证据强调了活动在形成视网膜原基连接的精细化中的作用，但这些过程背后的细胞和分子机制仍然是一个激烈调查的主题。我们建立了一个啮齿动物视觉系统发育的模型，在该模型中，我们描述了出生后早期外侧膝状体(LGN)发生的结构和功能变化。我们的实验表明，视黄醇原性轴突构型和连通性的变化与Hebbian样突触强度的改变和L型钙通道的激活有关。然而，L类钙离子通道在视网膜原核发育过程中的作用及其表达在很大程度上尚不清楚。这个项目的主要目的是研究出生后早期L类钙离子活性的性质，并建立这种活性与视黄素生成连接重塑之间的直接联系。我们将利用电生理学、解剖学和生化技术来描述L钙通道表达的性质及其在视网膜原细胞发育中的作用。我们将利用转基因小鼠的优势，在转基因小鼠中，通过定向删除钙通道的Beta2或Beta3亚基，L类型的钙活性和通道表达已经严重减弱。这些小鼠提供了一个独特的机会，将L型钙离子功能与LGN的突触稳定和活性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.