Depression of Inhibitory Synaptic Transmission between Purkinje Cells and Neurons of the Cerebellar Nuclei

Abstract

Neurons of the cerebellar nuclei have basal firing rates of 10-20 Hz, despite the convergence of many GABAergic Purkinje terminals onto cerebellar nuclear somata and the high spontaneous firing rate of Purkinje neurons. This persistence of firing during a constant barrage of inhibition raises the question of what patterns of Purkinje cell input inhibit nuclear cells most effectively. To explore the hypothesis that synaptic depression moderates inhibition at this synapse, we made whole-cell recordings from cerebellar nuclear neurons in mouse brain slices. IPSCs and IPSPs were elicited by electrically stimulating the corticonuclear tract at 10, 50, and 100 Hz. IPSCs evoked at the mean spontaneous firing rate of Purkinje cells (50 Hz) depressed by approximately 60%. The onset of depression had a fast, frequency-dependent component, from which recovery was rapid (approximately 100 msec), and a slower, frequency-independent component, from which recovery was slow (approximately 10 sec). As stimulation rate increased, steady-state depression increased, but each IPSC decayed less completely between stimuli, producing a "tonic" IPSC. Changes in stimulation rate produced rapid changes in the level of depression. Under current clamp, cerebellar nuclear neurons fired spontaneously. During 50 Hz trains of IPSPs, firing was initially interrupted, but resumed coincident with the onset of depression. Low-frequency trains entrained postsynaptic firing, and high-frequency trains greatly slowed firing, primarily because of the tonic IPSC. Thus, the properties of depression at this synapse appear to limit the sensitivity of nuclear cells to basal inhibition, while allowing the cells to respond to increases and decreases in Purkinje cell activity.

Recurrent axon collaterals underlie facilitating synapses between cerebellar Purkinje cells

“…We find that PC-PC synapses facilitate for short interpulse intervals, whereas the paired-pulse ratio for PC-DCN synapses is close to 1 in organotypic cultures (23,24), and the synapse is strongly depressing in acute slices from rats (25) and mice (26,27). Concerning train behavior, PC-DCN synapses show moderate (23) or substantial (26,27) depression during trains, which contrasts with the summating response to trains found in the present work (Fig. 1).…”

Purkinje-Cell-Restricted Restoration of Kv3.3 Function Restores Complex Spikes and Rescues Motor Coordination inKcnc3Mutants

“…Rebound excitation is robust because each deep nuclear neuron receives synaptic input from up to ϳ30 Purkinje cells (Chan-Palay, 1977) during synchronized complex spike firing that is expected to exert powerful inhibitory effects through temporal summation. As a primarily depressing synapse, the Purkinje cell-to-DCN synapse is considerably more sensitive to sudden changes in Purkinje cell firing rate than tonic input at a constant frequency (Telgkamp and Raman, 2002;Pedroarena and Schwarz, 2003;Telgkamp et al, 2004). Given the enhancement of parallel fiber input to Purkinje cells (Matsukawa et al, 2003), it is unclear whether the decrease in spontaneous simple spike frequency described in slices generalize to Purkinje cells in vivo with intact parallel fibers.…”

“…Each complex spike consists of a brief burst of spikes at a very high frequency (Ͼ500 Hz). Postsynaptically to Purkinje cells, deep nuclear neurons are tonically inhibited (Telgkamp and Raman, 2002;Telgkamp et al, 2004) or temporally entrained by simple spike input (Gauck and Jaeger, 2000) and respond to complex spike input by strong inhibition followed by rebound excitation (Llinás and Mühlenthaler, 1988;Aizenman and Linden, 1999).…”

“…Each complex spike consists of a brief burst of spikes at a very high frequency (Ͼ500 Hz). Postsynaptically to Purkinje cells, deep nuclear neurons are tonically inhibited (Telgkamp and Raman, 2002;Telgkamp et al, 2004) or temporally entrained by simple spike input (Gauck and Jaeger, 2000) and respond to complex spike input by strong inhibition followed by rebound excitation (Llinás and Mühlenthaler, 1988;Aizenman and Linden, 1999).Given the putative roles of complex spikes in motor function, particularly in timing (Placantonakis et al, 2004), and the high frequency of sodium spikes within a complex spike, we hypothesized that altered complex spikes in Kcnc3-null mice underlie the observed motor deficits. To assess the role of Kv3.3 function in Purkinje cells, we restored Kv3.3 channels selectively in Purkinje…”

Axonal Propagation of Simple and Complex Spikes in Cerebellar Purkinje Neurons

“…Specifically, the most salient feature of poststimulus time histograms triggered to complex spikes in Purkinje neurons is an increase in cerebellar nuclear cell firing (McDevitt et al, 1987b), which makes a strong inhibitory role for the complex spike acting alone seem questionable. Cellular-level studies, however, provide evidence that cerebellar nuclear cell firing is highly sensitive to the frequency and amplitude of inhibitory inputs (Gauck and Jaeger, 2000;Telgkamp and Raman, 2002). Moreover, high-frequency synaptic inhibition can strengthen rebound firing of Purkinje cell targets (Aizenman and Linden, 1999;Sekirnjak and du Lac, 2002), which may trigger plasticity in both the cerebellar and vestibular nuclei (Aizenman et al, 1998;Nelson et al, 2003).…”