Dendritic Control of Spontaneous Bursting in Cerebellar Purkinje Cells

Abstract

We investigated the mechanisms that contribute to spontaneous regular bursting in adult Purkinje neurons in acutely prepared cerebellar slices. Bursts consisted of 3-20 spikes and showed a stereotypic waveform. Each burst developed with an increase in firing rate and was terminated by a more rapid increase in firing rate and a decrease in spike height. Whole-cell current-clamp recordings showed that each burst ended with a rapid depolarization followed by a hyperpolarization. Dual dendritic and somatic extracellular recordings revealed that each burst was terminated by a dendritic calcium spike. The contributions of T-and P/Q-type calcium current, large (BK) and small (SK) conductance calcium-activated potassium currents, and hyperpolarization-activated (I H ) current to bursting were investigated with specific channel blockers. None of the currents, except for P/Q, were required to sustain spontaneous bursting or the stereotypic burst waveform. T-type calcium, BK, and SK channels contributed to interspike and interburst intervals. The effect of T-type calcium channel block was more pronounced after BK channel block and vice versa, indicating that these two currents interact to regulate burst firing. Block of I H current had no effect on bursting. Partial block of P/Q-type calcium channels concurrently eliminated dendritic calcium spikes and caused a switch from regular bursting to tonic firing or irregular bursting. Dendritic calcium spikes persisted in the presence of tetrodotoxin, indicating that their initiation did not require somatic sodium spikes. Our results demonstrate an important role for dendritic conductances in burst firing in intact Purkinje neurons.

Cerebellar Ataxia by Enhanced CaV2.1 Currents Is Alleviated by Ca2+-Dependent K+-Channel Activators inCacna1aS218LMutant Mice

“…Yet, our data showed that apamin enhances burst firing in Cacna1a S218L Purkinje cells, which parallels the effects on WT Purkinje cell firing (Womack and Khodakhah, 2004). SK-channel activators, on the other hand, showed several positive effects on Cacna1a S218L Purkinje cell firing patterns in our in vitro experiments.…”

“…Thus, the combination of somatic and dendritic effects of the S218L mutation on Purkinje cell excitability appears to promote irregular activity patterns. Yet, we cannot rule out that our in vitro recording conditions may have, unlike those of other labs (Womack and Khodakhah, 2004;McKay and Turner, 2005), limited the occurrence of irregular Purkinje cell firing in WT (Häusser and Clark, 1997;Walter et al, 2006;Mark et al, 2011) and thus created a bias toward a larger effect of the S218L mutation.…”

“…6). Thus, it is likely that near the action potential initiation threshold Ca V 2.1-mediated currents in Cacna1a S218L Purkinje cells not only coincide with Na ϩ currents, but also evoke SK currents, a combination that is likely to affect Purkinje cell firing (Edgerton and Reinhart, 2003;Swensen and Bean, 2003;Womack and Khodakhah, 2004). Indeed, we found that during the bursting activity the action potential amplitude decreased and that long pauses consequently followed the bursts, which might be due to a decreased availability of Na ϩ channels and an elevated level of SK currents, respectively.…”

“…These data suggest that the more negative activation threshold of Ca V 2.1 channels in Cacna1a S218L Purkinje cells decreases the attenuation of somatic action potentials to such level that dendritic Ca V 2.1 channels can be activated and hence trigger dendritic Ca 2ϩ spikes. In turn, the subsequent activation of dendritic SK channels during burst firing could also affect somatic action potential firing (Womack and Khodakhah, 2004). Thus, the combination of somatic and dendritic effects of the S218L mutation on Purkinje cell excitability appears to promote irregular activity patterns.…”

Activation of Metabotropic Glutamate Receptors Induces Periodic Burst Firing and Concomitant Cytosolic Ca2+Oscillations in Cerebellar Interneurons

“…PCs fire bursts of action potentials that are inhibited by the stimulation of complex spikes by CFs (Tank et al, 1988;Cerminara and Rawson, 2004;Womack and Khodakhah, 2004). The present demonstration, that in certain conditions MLIs can similarly adopt a periodic bursting pattern, raises the possibility that in these conditions, MLIs and postsynaptic PCs could oscillate in phase opposition.…”