Imaging Synaptic Plasticity in the Visual Cortex in Vivo

描述(申请人提供)：这项资助建议确定快速放电抑制神经元的双眼激活是否在抑制输出到锥体的成熟的上游，以及抑制的成熟是否指导视觉皮质双眼区域内兴奋性连接的连接。我们的研究利用双光子视觉引导的松散细胞附着和全细胞电压钳记录锥体神经元和表达小白蛋白的中间神经元。通过操纵NeuRegin/ErbB4信号通路来促进或损害表达小白蛋白的中间神经元的成熟，以确定这种抑制是否指导了兴奋性输入在体内对锥体神经元的适当成熟。NeuRegin/ErbB4信号通路与精神分裂症有关，精神分裂症被认为是由于抑制招募中的发育障碍造成的。拟议的研究结果将确定特定类别的抑制性神经元的招募与正常兴奋性皮质回路和反应性的建立之间的相互关系。这些结果将确定对抑制性成熟最敏感的发育时期，为精神分裂症的研究提供重要的新信息。 与公共健康相关：这项工作将为控制大脑皮质发育中抑制招募的机制提供基本的见解，并将确定抑制的成熟是否指导皮层兴奋性连接的连接。重点是研究NeuRegin/ErbB4信号在这一过程中的作用-这两个都是精神分裂症的易感基因。我们的数据将为精神分裂症的发展提供洞察，确定对干预影响最大的发育阶段。

DESCRIPTION (provided by applicant): This grant proposes to determine whether binocular activation of fast-spiking inhibitory neurons is upstream of the maturation of inhibitory output onto pyramids, and whether maturation of inhibition directs wiring of excitatory connections within the binocular zone of visual cortex. Our studies utilize 2-photon visually guided loose cell attached and whole cell voltage clamp recordings of pyramidal neurons and parvalbumin-expressing interneurons. Manipulations of the Neuregulin/ErbB4 signaling pathway are used to accelerate or impair the maturation specifically of parvalbumin- expressing interneurons to determine whether this inhibition guides the appropriate maturation of excitatory input onto pyramidal neurons in vivo. The Neuregulin/ErbB4 signaling pathway is implicated in schizophrenia, a disease thought to result from a developmental impairment in the recruitment of inhibition. Results from the proposed studies will determine the interrelationship between the recruitment of a specific class of inhibitory neurons and the establishment of normal excitatory cortical circuitry and responsiveness. These results will identify developmental epochs of highest sensitivity to inhibitory maturation, providing important new information with strong relevance to schizophrenia research. PUBLIC HEALTH RELEVANCE: This work will provide fundamental insights into mechanisms that control the recruitment of inhibition in developing cortex and will determine whether maturation of inhibition directs wiring of excitatory connections in cortex. Emphasis is placed on examining the role of Neuregulin/ErbB4 signaling in this process - both schizophrenia susceptibility genes. Our data will provide insight into the development of schizophrenia, identifying developmental stages with the highest impact for intervention.