Alcohol and cerebellar circuits

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DESCRIPTION (provided by applicant): Acute and long-term ethanol (EtOH) exposure produces cerebellar dysfunction, leading to alterations in gait, balance and coordination that are responsible for a large number of injuries and deaths in the United States. Recent evidence indicates that EtOH affects executive functions and this could be a consequence of disruptions in frontocerebellar circuitry. However, our understanding of the mechanism of action of EtOH in the cerebellum is still in its infancy. Excitatory input from the brain stem and spinal cord enters the cerebellar cortex at the granule cells via the mossy fibers. These neurons also receive inhibitory input from the Golgi cells, which are the major granule cell layer interneuronal subtype. Golgi cells, in turn, receive feedforward excitatory input from mossy fibers, feedback excitatory input from granule cell axons and inhibitory input from molecular layer interneurons. Our overarching hypothesis is that acute EtOH exposure impairs the normal functioning of granule layer circuitry by decreasing glutamatergic and increasing GABAergic transmission at both granule and Golgi cells. Specific Aim #1 is to characterize the effect of EtOH on glutamatergic transmission at granule cells. During the previous funding period, we determined that EtOH increases tonic and phasic GABAergic input to granule cells without affecting spontaneous glutamatergic transmission mediated by AMPA receptors. Using the acute cerebellar slice preparation and patch-clamp electrophysiological techniques, we will now study the effect of EtOH on NMDA receptor function and long- term potentiation at mossy fiber-to-granule cell synapses. We will investigate its effects on granule cell activation by sensory-like patters of mossy fiber activation; for these studies, single-neuron recordings will be complemented by autofluorescence optical imaging of [the mossy fiber area of activation]. Specific Aim #2 is to further characterize the effects of EtOH on Golgi cells. During the previous funding period, we demonstrated that EtOH increases Golgi cell firing and propose to characterize the mechanism responsible for this effect. [Based on a combination of computer modeling and experimental studies, we propose to characterize IA, Na+/K+ pump and persistent Na+ currents as potential mediators of EtOH's effect]. We will also investigate EtOH's effect on GABAergic and/or glutamatergic input to Golgi cells. These studies with acute slices will be complemented with in vivo electrophysiological experiments of the acute effects of EtOH on the function of these neurons. In Specific Aim #3, we will investigate the effect of EtOH on network activity in the granule cell layer as a whole using a data-driven computational neuroscience approach. These multidisciplinary studies will significantly increase our understanding of the acute effects of EtOH on the cerebellar granule cell layer, forming the basis for the identification of new targets for therapeutic interventions against EtOH-induced cerebellar dysfunction.