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Presynaptic Modulation of Synaptic Inhibition onto Hippocampal Pyramidal Neurons

海马锥体神经元突触抑制的突触前调节

基本信息

批准号：
10863330
负责人：
Annalisa Scimemi
金额：
$ 46.11万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10863330
关键词：
Animals Area Behavior Brain Cells Cerebrospinal Fluid Code Cognitive Complex Cues Data Development Diffuse Diffusion Disease Distal Electron Microscopy Electrophysiology (science)Epilepsy Evaluation Family Feedback Functional disorder Future Gatekeeping Glutamate Receptor Glutamate Transporter Glutamates Goals Hippocampus In Vitro Inhibitory Synapse Interneurons Investigation Knowledge Location Maps Membrane Potentials Memory Metabotropic Glutamate Receptors Mus Output Parvalbumins Physiological Physiology Population Heterogeneity Positioning Attribute Pyramidal Cells Reporting Role Running Sensory Shapes Signal Pathway Signal Transduction Slice Somatostatin Synapses Synaptic Cleft Synaptic Transmission Training Transgenic Mice Trees Vesicle Work autism spectrum disorder differential expression experimental study extracellular gamma-Aminobutyric Acid hippocampal pyramidal neuron in vivo information processing insight metabotropic glutamate receptor 4 metabotropic glutamate receptor 8 nervous system disorder neural circuit neuronal circuitry neurotransmitter release new therapeutic target optogenetics patch clamp pharmacologic place fields presynaptic receptor recruit spatiotemporal synaptic function synaptic inhibition way finding

项目摘要

PROJECT SUMMARY Throughout the hippocampus, pyramidal cells integrate excitatory and inhibitory inputs from a diverse population of interneurons. These cells provide feedforward and feedback inhibition onto CA1 pyramidal cells, and can be recruited via glutamate spillover, a phenomenon that describes non-synaptic actions of glutamate diffusing away from the synaptic cleft. The current prevailing view is that glutamate spillover leads to activation of presynaptic group III metabotropic (mGluRIII) glutamate receptors, which inhibit synaptic excitation and inhibition only onto interneurons, not CA1 pyramidal cells. Against this interpretation, our preliminary data indicates that spillover activation of mGluRIII receptors also exists at inhibitory synapses formed onto CA1 pyramidal cells. The main goals in this application are: (i) to determine how mGluRIII activation via glutamate spillover varies between excitatory and inhibitory inputs, and among inhibitory inputs formed by different classes of interneurons; (ii) to identify the intracellular signaling mechanisms that couple mGluRIII activation to neurotransmitter release; (iii) the determine the sub-cellular location of different type of mGluRIII receptors at different types of inhibitory synapses onto CA1 pyramidal cells; (iv) to determine how spillover activation of mGluRIII alters encoding of spatial information by hippocampal CA1 place cells in vivo. The proposed experiments capitalize on in vitro and in vivo electrophysiology, and EM approaches. These findings will generate new information on the operating principles of neuronal circuits involved in spatial map representation and will contribute to the future development of effective strategies to treat disease states associated with hippocampal neural circuit dysfunction, like epilepsy and autism spectrum disorder.

项目总结在整个海马区，锥体细胞整合来自不同来源的兴奋性和抑制性输入中间神经元的数量。这些细胞对CA1锥体细胞提供前馈和反馈抑制，并且可以通过谷氨酸溢出来招募，谷氨酸溢出是一种描述谷氨酸的非突触行为的现象从突触裂隙扩散开来。目前流行的观点是谷氨酸溢出导致激活突触前III组代谢性(MGluRIII)谷氨酸受体，它抑制突触兴奋和仅对中间神经元有抑制作用，对CA1锥体细胞无抑制作用。与这种解释相反，我们的初步数据提示在CA1上形成的抑制性突触上也存在mGluRIII受体的溢出激活锥体细胞。本申请的主要目标是：(I)确定mGluRIII是如何通过谷氨酸激活的兴奋性输入和抑制性输入之间以及不同类别形成的抑制性输入之间的溢出效应不同 (Ii)确定将mGluRIII激活偶联到神经递质释放；(Iii)确定不同类型mGluRIII受体的亚细胞位置不同类型的抑制性突触连接到CA1锥体细胞；(Iv)确定外溢激活如何 MGluRIII改变了体内海马CA1区细胞对空间信息的编码。建议数实验利用了体外和体内的电生理学和EM方法。这些发现将产生关于参与空间地图表示和意志的神经元电路工作原理的新信息有助于未来制定有效的策略来治疗与海马体相关的疾病状态神经回路功能障碍，如癫痫和自闭症谱系障碍。