The cerebellum is involved in motor control, and disruption of its function can lead to a variety of movement disorders. Purkinje neurons of the cerebellar cortex, which integrate signals from many brain regions, form inhibitory synapses onto neurons of the cerebellar nuclei, which project widely. Despite the importance of this synapse in cerebellar function, the electrical properties of cerebellar nuclear neurons are largely unknown. These neurons fire spontaneous action potentials, even during high rates of spontaneous inhibition from Purkinje neurons. This persistence of activity must partly result from the properties of ion channels intrinsic to cerebellar nuclear neurons. Additionally, rapid signaling in Purkinje cells may lead to a depletion of neurotransmitter, reducing the level of postsynaptic inhibition. The proposed experiments will identify ionic currents underlying spontaneous firing in cerebellar nuclear neurons, as well as determine the patterns of inhibitory synaptic input from Purkinje cells that successfully modulate firing in cerebellar nuclear neurons. Understanding this interaction between synaptic and intrinsic currents is central to understanding a basic element of the neural code, specifically, whether synaptic inhibition necessarily silences a postsynaptic cell or whether it sometimes enables or enhances firing. Cerebellar nuclear neurons will by enzymatically isolated from young mice and used for high-quality voltage-clamp recordings of currents that are pharmacologically isolated with channel-specific blockers. Currents will be evoked by voltage-clamp commands consisting of action potential waveforms, allowing direct measurements of the currents contributing to firing. Cerebellar slices, under visual control, will be used to make recordings of responses of cerebellar nuclear neurons to high- and low- frequency firing evoked in Purkinje neurons. Such experimental measures of the currents in specific neuronal classes is essential to the development of accurate computer models of neural activity, as well as to cellular interpretations of systems-level studies of cerebellar function and dysfunction.
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