Plasticity of intrinsic excitability and excitatory synaptic transmission in the deep cerebellar nuclei of the rat

The deep cerebellar nuclei (DCN) are the major output of the cerebellum which play a major role in certain forms of motor learning, most notably associative eyeblink conditioning. Several lines of evidence suggest that the DCN are involved in memory acquisition and storage of associative eyeblink conditioning. Lesions, reversible inactivation and local blockade of protein synthesis in the DCN can prevent acquisition of conditioned eyelid response when applied before training, and can eliminate the memory for training when applied afterwards (Clark et al., 1992; Krupa et al., 1993; Bracha et al., 1998). Despite this evidence, DCN neurons remain poorly characterized at the cellular level, and relatively few electrophysiological studies have been performed. In this study, I combine microelectrode intracellular recording, whole-cell current-clamp recording and Ca2+ imaging to characterize intrinsic plasticity in DCN neurons and synaptic plasticity at the mossy fiber-DCN synapse.; In characterizing intrinsic plasticity in the DCN, I have sought to address the following questions. What electrophysiological sequelae accompany the induction in intrinsic excitability increases? Can increases in intrinsic excitability be manifested as changes in firing pattern? What is the range of stimuli that can induce increases in intrinsic excitability? I found in tonically firing DCN neurons, a stimulus consisting of EPSP bursts produced a brief increase in dendritic Ca2+ concentration and a persistent increase in the number of spikes elicited by a depolarizing test pulse, along with a decrease in spike threshold. In intrinsically bursting DCN neurons, EPSP bursts induced an increase in the number of depolarization-evoked spikes in some neurons, but in others produced a change to a more tonic firing pattern. Application of IPSP bursts evoked a large number of rebound spikes and an associated dendritic Ca2+ transient, which also produced a persistent increase in the number of spikes elicited by a test pulse. Intracellular perfusion of the Ca2+ chelator BAPTA prevented the increase in intrinsic excitability. Thus, rapid changes in intrinsic excitability in the DCN may be driven by bursts of both EPSPs and IPSPs, and may result in persistent changes to both firing frequency and pattern.; In addition to modification of intrinsic excitability in DCN, I also want to know whether behaviorally salient patterns of synaptic activation can give rise to a long-term plasticity at the mossy fiber-DCN synapse. I found that high frequency burst stimulation of mossy fibers, either alone or paired with postsynaptic depolarization, resulted in a long-term depression (LTD) of the mossy fiber-DCN synapse. This form of LTD is not associated with changes in the paired pulse ratio and is blocked by loading with a postsynaptic Ca2+ chelator but not by bath application of an NMDA receptor antagonist. Mossy fiber-DCN LTD requires activation of a group I mGluR and protein translation. Unlike mGluR/translation-dependent LTD in other brain regions, this form of LTD requires mGluR1 and is mGluR5-independent. Modification of intrinsic excitability in the DCN and plasticity at the mossy fiber-DCN synapse are both potential cellular explanations for the associative eyeblink conditioning memory trace.