NEURONAL PLASTICITY IN RETINAL CIRCUIT DEVELOPMENT

描述（由申请人提供）：发展中的神经回路经历了一个关键时期，以建立精确的连接。在这些关键时期，神经元活动和程序性细胞死亡（PCD）塑造了神经元的解剖结构和功能（即神经元可塑性）。可塑性失调已被确定为自闭症和精神分裂症等神经发育障碍病因学的共同步骤。神经元的可塑性包括轴突和树突的重塑、突触的形成和消除、突触前和突触后特化的分子结构的变化以及对内在兴奋性的调整。虽然我们对个体可塑性机制的调节和作用已经了解得很多，但在神经发育过程中，不同的可塑性机制是如何合作的还不是很清楚。最近的证据表明，这些机制之间的串扰决定了它们的功能，并表明可塑性机制的相互作用取决于神经元类型和体内回路环境。在这里，我们建议研究不同的可塑性机制是如何在体内不同水平的神经组织（突触、神经元和回路）中合作的

DESCRIPTION (provided by applicant): Developing neural circuits undergo critical periods of refinement to establish precise connectivity. During these critical periods, neuronal activity and programmed cell death (PCD) shape the anatomy and function of neurons (i.e. neuronal plasticity). Dysregulation of plasticity has been identified as a common step in the etiology of neurodevelopmental disorders such as autism and schizophrenia. Neuronal plasticity encompasses axon and dendrite remodeling, synapse formation and elimination, changes in the molecular architecture of pre- and postsynaptic specializations, and adjustments to intrinsic excitability. While much is known about the regulation and action of individual plasticity mechanisms, how different plasticity mechanisms cooperate during neural development is not well understood. Recent evidence indicates that crosstalk between these mechanisms governs their function , and suggests that the interplay of plasticity mechanism depends on neuron type and in vivo circuit context. Here, we propose to study how diverse plasticity mechanisms cooperate across different levels of in vivo neural organization (synapse, neuron and circuit), in different cellular compartments (dendrite and axon), and in response to different triggers (neuronal activity and PCD) to shape the development and function of retinal bipolar cells (BCs), glutamatergic second order neurons of the visual system. Towards this end, we have generated transgenic mouse lines that selectively interfere with synaptic input to or output from BCs, or in which BCs can be removed in a graded manner concurrent with their naturally occurring PCD. To analyze structural and functional plasticity, we have established optical approaches from superresolution microscopy, to confocal reconstructions and 2-photon live imaging and optimized methods for targeted patch-clamp and anatomically aligned multielectrode array (MEA) recordings. Thus, we aim to provide an integrated view how diverse activity- and cell- density-dependent plasticity mechanisms cooperate to guide the development of a specific class of neurons and their integration into precise circuits in vivo.