Cellular mechanisms of GABAergic inhibition in neocortical dendrites

描述（由申请人提供）：皮质GABA能中间神经元（IN）在控制大脑活动的正常模式中起关键作用，并涉及脑缺血的病理生理学。 神经精神疾病。虽然许多IN靶向锥体神经元（PN）胞体，在那里它们调节尖峰输出的幅度和定时，但大多数GABA能突触形成于PN树突上，其中它们在细胞功能中的作用尚不清楚。树突靶向的中间神经元，表达肽生长抑素（SOM-INs）的假设提供负反馈的远端PN树突，规模与当地的网络活动。然而，技术限制，选择性地控制这些神经元的输出，同时测量树突状细胞的活动与高空间分辨率，阻止了一个清晰的阐述SOM-IN功能。我们的长期目标是了解不同的GABA能IN池如何促进前额叶皮层（PFC）的细胞和回路调节， 与高级认知过程有关的区域，可能在精神分裂症等疾病中被破坏。在这个提议中，我们的主要目标是确定SOM-INs如何调节PFC PN树突中的钙（Ca）信号。我们还专注于了解树突抑制是如何形成的PN树突和神经调质多巴胺的内在电压门控特性。我们的中心假设是，GABA能抑制是异质性和分隔在PN树突。我们预期这种区室化依赖于许多因素，包括抑制性突触激活的时空模式和树突结构（如棘）的电特性。在强有力的初步数据的指导下，我们将从三个具体目标来检验这一中心假设：1）确定GABA能抑制在塑造树突Ca信号传导中的作用。2)确定电压门控树突电导有助于抑制性突触整合。3)确定多巴胺对树突抑制和Ca信号传导的作用。这些实验产生的数据将产生新的见解GABA能传输的神经元细胞生物学和皮层电路的功能的贡献。我们希望我们的研究结果也能为GABA能和多巴胺能信号紊乱引起的神经精神疾病的病理生理学研究提供新的途径。 公共卫生相关性：抑制性GABA能神经元对新皮层神经元的活动提供重要控制。这项提议将确定GABA能突触在调节皮质神经元树突内钙（一种关键的生化信号分子）中的作用。这些研究的结果将有助于确定新的细胞机制，可能有助于神经精神疾病的病理生理学，并提出新的治疗干预途径。

DESCRIPTION (provided by applicant): Cortical GABAergic interneurons (INs) play critical roles in controlling normal patterns of brain activity and are implicated in the pathophysiology of neuropsychiatric disease. While many INs target pyramidal neuron (PN) somata, where they regulate the magnitude and timing of spike output, the majority of GABAergic synapses are formed onto PN dendrites, where their role in cellular function is less well understood. Dendrite-targeting interneurons that express the peptide somatostatin (SOM-INs) are hypothesized to provide negative feedback to distal PN dendrites that scales with local network activity. However, technical limitations to selectively controlling the output of these neurons while simultaneously measuring dendritic activity with high spatial resolution have prevented a clear elaboration of SOM-IN function. Our long-term goal is to understand how distinct pools of GABAergic INs contribute to cellular and circuit regulation in the prefrontal cortex (PFC), a brain region associated with higher cognitive processes that may be disrupted in illnesses such as schizophrenia. In this proposal, our primary objective is to identify how SOM-INs regulate calcium (Ca) signaling in the dendrites of PFC PNs. We also focus on understanding how dendritic inhibition is shaped by the intrinsic voltage-gated properties of PN dendrites and the neuromodulator dopamine. Our central hypothesis is that GABAergic inhibition is both heterogeneous and compartmentalized in PN dendrites. We expect that this compartmentalization is dependent on many factors, including the spatiotemporal pattern of inhibitory synaptic activation and the electrical properties of dendritic structures such as spines Guided by strong preliminary data, we will examine this central hypothesis in three specific aims: 1) Determine the role of GABAergic inhibition in shaping dendritic Ca signaling. 2) Identify the voltage-gated dendritic conductances that contribute to inhibitory synaptic integration. 3) Determine the actions of dopamine on dendritic inhibition and Ca signaling. The data generated by these experiments will generate new insights into the contribution of GABAergic transmission to both neuronal cell biology and the function of cortical circuits. We expect our results will als highlight new avenues into the investigation of the pathophysiology underlying neuropsychiatric disorders resulting from perturbation of both GABAergic and dopaminergic signaling. PUBLIC HEALTH RELEVANCE: Inhibitory GABAergic neurons provide important control over the activity of neurons in the neocortex. This proposal will determine the role of GABAergic synapses in regulating calcium, a key biochemical signaling molecule, within the dendrites of cortical neurons. Results from these studies will help identify novel cellular mechanisms that may contribute to the pathophysiology of neuropsychiatric disorders and suggest new avenues for therapeutic intervention.