Mechanisms regulating formation and maintenance of sensory circuits

位于感觉神经元轴突终末的突触前抑制性突触严格调节 信息在感觉回路中流动，允许有机体与其外部的有意义的相互作用。 环境尽管我们对突触前抑制性突触的功能作用了解很多， 感觉电路;很少有人知道的机制，调节发展，成熟和 维持这些抑制性突触。使用具有良好特性的微光（杆）视觉电路， 我们发现在GABA能突触前抑制蛋白的组装过程中， 调节视网膜暗光输出的突触目前的建议旨在确定细胞自主和 非细胞自主机制，调节这种发育可塑性在组装抑制 调节感觉（视网膜）信号传输增益的反馈电路。我们的研究将产生基础性的 有关信息：（i）视网膜电路组件（ii）感觉电路和调节机制的组织 感觉反馈，以及（iii）在抑制回路建立过程中调节受体可塑性的原理 穿过CNS。我们将联合收割机小鼠转基因方法与高分辨率光学显微镜、3D 电子显微镜和电生理学，以解决以下三个目标。在目标1中，我们将确定是否细胞自主改变氯转运蛋白表达在整个发展视网膜杆双极神经元驱动 并调节发育性GABAA受体重组的时间和/或发生。目标2将 确定兴奋性和抑制性神经传递对视网膜杆双极神经元的贡献， 调节发育中GABAA受体的可塑性。目标3将决定早期视觉经验的作用 在调节GABAA受体重组和装配的反馈抑制性突触的昏暗的光 视网膜回路我们的研究将揭示细胞自主机制，突触输入， 反馈抑制回路的建立和成熟过程中的网络活动和环境线索， 调节感觉输出。我们的研究还将揭示电路可塑性基序，可以招募改善 视网膜疾病期间的功能障碍此外，我们的研究结果将确定的发展顺序， 体内突触前抑制回路组装过程中的成熟与离体视网膜组装进行比较， 如当多能干细胞用于视网膜生成时。

Presynaptic inhibitory synapses positioned across axon terminals of sensory neurons critically regulate information flow across sensory circuits, allowing meaningful interactions of an organism with its external environment. Whereas much is known about the functional role of presynaptic inhibitory synapses across sensory circuits; little is known about the mechanisms that regulate the development, maturation and maintenance of these inhibitory synapses. Using the well-characterized dim-light (rod) visual circuit of the mammalian retina we uncovered a synaptic reorganization during assembly of GABAergic presynaptic inhibitory synapses that regulate dim-light retinal output. The current proposal aims to determine the cell-autonomous and non-cell autonomous mechanisms that regulate this developmental plasticity during assembly of inhibitory feedback circuits that regulate the gain of sensory (retinal) signal transfer. Our research will yield fundamental information about: (i) retinal circuit assembly (ii) organization of sensory circuits and mechanisms that regulate sensory feedback, and (iii) principles that regulate receptor plasticity during establishment of inhibitory circuits across the CNS. We will combine murine transgenic approaches with high resolution light microscopy, 3D electron microscopy and electrophysiology to address the following three Aims. In Aim 1 we will determine if cell-autonomous alterations in chloride transporter expression across developing retinal rod bipolar neurons drive and regulate the timing and/or occurrence of the developmental GABAA receptor reorganization. Aim 2 will determine the contribution(s) of excitatory and inhibitory neurotransmission onto the retinal rod bipolar neuron in regulating the developmental GABAA receptor plasticity. Aim 3 will determine the role of early visual experience in regulating GABAA receptor reorganizations and assembly of feedback inhibitory synapses of the dim-light retinal circuit. Our research will reveal the interplay between cell-autonomous mechanisms, synaptic input, network activity and environmental cues during establishment and maturation of feedback inhibitory circuits that regulate sensory output. Our study will also reveal circuit plasticity motifs that can be recruited to ameliorate dysfunction during retinal diseases. Furthermore, our findings will determine the developmental sequence of maturation during assembly of invivo presynaptic inhibitory circuits to compare with exvivo retinal assembly such as when pluripotent stem cells are used for retinogenesis.