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

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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.