Electrogenic Dendrites of the Deep Cerebellar Nuclei

Abstract

The purpose of this thesis is to investigate whether neurons of the deep cerebellar nuclei (DCN) have active dendrites. DCN neurons are the critical output of the cerebellum, essential to all behaviors in which the cerebellum is involved and necessary for the consolidation of learning in the cerebellum. Despite their importance in the cerebellar circuit our understanding of the biophysical properties of these neurons is scant. Early work hints at the possibility that deep nuclear neurons might have active dendrites. If dendrites were capable of local amplification of synaptic input, they would provide a stage of integration prior to the neuron's spike output, and also provide a means by which plasticity could be determined by events occurring near the location of synapses. Experiments contained in this thesis demonstrate for the first time that DCN neurons exhibit three of the hallmarks of active dendrites found elsewhere in the central nervous system (CNS). First, they produce large dendritic calcium spikes comparable in amplitude to dendritic action potentials in other CNS neurons. Second, dendritic calcium signals do not diminish with distance from the soma, as would be expected for passive backpropagation. Third, DCN dendrites can generate calcium signals even in the presence of tetrodotoxin, a sodium channel blocker that abolishes action potential firing in vertebrate neurons. Instead, DCN calcium transients require the action of T-type calcium current, a voltage-gated conductance found in many other excitable dendrite types. Together these results suggest that DCN neurons have active dendrites capable of processing separate from the soma. Finally, the ability of DCN dendrites to generate calcium spikes is considerably enhanced by the addition of phorbol-12-myristate-13-acetate, an activator of the G protein-coupled receptor target protein kinase C (PKC). Thus the excitability of DCN dendrites may be increased under the influence of neuromodulators, which are known to regulate attention, learning, and a host of other systems-level functions.