Cellular mechanisms of GABAergic inhibition in neocortical dendrites

描述(申请人提供)：皮质GABA能中间神经元(INS)在控制正常的脑活动模式中起关键作用，并与脑血管疾病的病理生理学有关。 神经精神疾病。虽然许多INS以锥体神经元(PN)胞体为靶点，在那里它们调节尖峰输出的幅度和时间，但大多数GABA能突触形成在PN树突上，在那里它们在细胞功能中的作用尚不清楚。树突靶向中间神经元表达生长抑素(SOM-INS)肽(SOM-INS)被认为是向远端的PN树突提供负反馈，该反馈随局部网络活动而扩大。然而，选择性地控制这些神经元的输出同时以高空间分辨率测量树突状细胞活动的技术限制阻碍了对SOM-IN功能的明确阐述。我们的长期目标是了解不同的GABA能INS池如何对大脑前额叶皮质(PFC)的细胞和电路调节做出贡献 与较高认知过程相关的区域，在精神分裂症等疾病中可能会中断。在这个方案中，我们的主要目标是确定SOM-ins如何调节PFC PNS树突中的钙(Ca)信号。我们还重点了解树突抑制是如何由PN树突和神经调节剂多巴胺的内在电压门控属性塑造的。我们的中心假设是，GABA能抑制在PN树突中既是异质性的，又是区域化的。我们预计这种划分取决于许多因素，包括抑制性突触激活的时空模式和树突结构的电特性，在强大的初步数据的指导下，我们将从三个具体的目的来检验这一中心假说：1)确定GABA能抑制在形成树突状钙信号中的作用。2)确定参与抑制性突触整合的电压门控树突电导。3)确定多巴胺对树突抑制和钙信号转导的作用。这些实验产生的数据将对GABA能传递对神经细胞生物学和皮质回路功能的贡献产生新的见解。我们预计我们的结果将为研究GABA能和多巴胺能信号扰动引起的神经精神障碍的病理生理学提供新的途径。

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.