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Subcellular Localization of Glutamate Spillover on to Inhibitory Interneurons in the Cerebellar Cortex

谷氨酸溢出到小脑皮质抑制性中间神经元的亚细胞定位

基本信息

批准号：
10285980
负责人：
Reagan Pennock
金额：
$ 3.37万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10285980
关键词：
AMPA Receptors Address Anatomy Area Ataxia Axon Biomedical Research Brain Cerebellar Cortex Cerebellar Diseases Chemosensitization Code Data Dendrites Disease Electric Stimulation Electrophysiology (science)Fiber Frequencies Fright Glutamate Receptor Glutamates Image Imaging Techniques Individual Inferior Institution International Interneurons Knowledge Learning Location Maps Measures Mediating Memory Mentors Methods Motor Movement Movement Disorders Neurologic Olives - dietary Output Pattern Permeability Pharmacology Physiological Physiology Plant Roots Play Process Purkinje Cells Research Resolution Role Schizophrenia Shapes Signal Transduction Slice Spatial Distribution Structure of molecular layer of cerebellar cortex Synapses Synaptic Transmission Synaptic plasticity Testing Training autism spectrum disorder executive function experimental study granule cell in vivo information processing insight meetings neurotransmission receptive field receptor recruit response responsible research conduct segregation spatiotemporal transmission process two photon microscopy two-photon

项目摘要

Information processing by the cerebellar cortex is widely accepted to be critical for the execution of coordinated movement, and has more recently been shown to play a role in executive control, spatial learning and memory, and fear responses. Therefore, understanding neurotransmission within the cerebellar cortex is not only important for understanding the root cause of movement disorders such as ataxias, but also in disorders involving higher brain functions. Indeed, cerebellar dysfunction has been shown to be related to schizophrenia and autism. Molecular layer interneurons (MLIs) shape the output of the cerebellar cortex through feed-forward inhibition of neighboring Purkinje cells, as well as neighboring MLIs. Feed-forward inhibition is driven by conventional point-to-point synaptic transmission from parallel fiber axons (PFs), as well as by unconventional spillover transmission from nearby climbing fiber (CF)-PC synapses. CF spillover onto MLIs has been shown to be sufficient to drive MLI firing, and thus feed-forward inhibition, and in vivo studies have demonstrated that CF-MLI transmission can induce potentiation of PF-MLI inputs. However, the subcellular basis for this unconventional form of neurotransmission has yet to be elucidated. The experiments in this proposal will employ Ca2+ imaging, electrophysiology, and pharmacology to determine: 1) the subcellular distribution of receptors activated by glutamate spillover onto MLI dendrites. This distribution will be determined for glutamate receptors activated by spillover from CF-PC synapses, as well as spillover resulting from physiologically relevant stimulation of PF-MLI synapses. This pattern of activation will then be compared to that of synaptic glutamate receptors, which can be isolated pharmacologically from spillover-activated receptors. 2) The relationship between the spatial extent of CF spillover onto MLIs and CF- induced plasticity at PF-MLI synapses. Specifically, whether CF-induced plasticity of PF-MLI synapses is confined to areas that directly receive glutamate spillover from CF-PC synapses will be determined. Completion of this project will provide insight into an important but sparsely studied form of transmission that is required to understand information processing within the cerebellar cortex, and will provide the trainee with extensive training in two-photon imaging, synaptic physiology, and expand the trainees knowledge of pharmacology. This research will be carried out at a leading biomedical research institution, and the training plan includes opportunities to present at national and international meetings, regular formal and informal interactions with the sponsor and co-sponsor, and formal and informal mentoring in the responsible conduct of research.

小脑皮层的信息处理被广泛认为是执行任务的关键