Neurons of the cerebellar nuclei are spontaneously active neurons that integrate excitatory input from mossy fibers and inhibitory input from Purkinje neurons to generate the output of the cerebellum. The strength and extent of Purkinje input raise the question of how inhibition interacts with excitation and intrinsic firing to regulae cerebellar output. Because Purkinje cells can synchronize their simple spikes during cerebellar behaviors, it is likely that cerebellar nuclear neurons respond to the degree of synchrony of inhibitory inputs, with more temporally dispersed inhibition from Purkinje cells providing a more effective shunt of nuclear cell spiking, and more synchronized inhibition leading to reductions in net inhibition that allow spikes to occur. The present proposal is directed toward testing the idea that inhibitory synchrony has a significant effect on dictating cerebellar output under normal conditions, as well as toward examining the possibility that Purkinje-to-nuclear cell signaling may be modulated naturally or change under pathophysiological conditions. Experiments will be performed both in vitro and in vivo, on normal and mutant mice and in zebrafish. Voltage-clamp, current-clamp, and extracellular recordings will be used to test the interaction of excitatory with inhibitory inputs, the consequences of modulating Purkinje inputs, and the effect of sensory input on Purkinje synchrony and nuclear cell output.
The cerebellum regulates movements and various aspects of cognitive function, and its dysfunction is associated with ataxia, dystonia, dyslexia, and autism. Information about sensory signals are received by Purkinje neurons in the cerebellum, which then modify the information and send it to neurons in the cerebellar nuclei, which further process the information and then send it to parts of the brain that control the timing and sequencing of behaviors. In the present application, we propose to study how signals are transmitted and transformed as they go from Purkinje neurons to neurons in the cerebellar nuclei, and what changes arise in disorders such as autism.
