Effects of Climbing Fiber Driven Inhibition on Purkinje Neuron Spiking

Abstract

Climbing fiber (CF) input to the cerebellum is thought to instruct associative motor memory formation through its effects on multiple sites within the cerebellar circuit. We used adeno-associated viral delivery of channelrhodopsin-2 (ChR2) to inferior olivary neurons to selectively express ChR2 in CFs, achieving nearly complete transfection of CFs in the caudal cerebellar lobules of rats. As expected, optical stimulation of ChR2-expressing CFs generates complex spike responses in individual Purkinje neurons (PNs); in addition we found that such stimulation recruits a network of inhibitory interneurons in the molecular layer. This CF-driven disynaptic inhibition prolongs the postcomplex spike pause observed when spontaneously firing PNs receive direct CF input; such inhibition also elicits pauses in spontaneously firing PNs not receiving direct CF input. Baseline firing rates of PNs are strongly suppressed by low-frequency (2 Hz) stimulation of CFs, and this suppression is partly relieved by blocking synaptic inhibition. We conclude that CF-driven, disynaptic inhibition has a major influence on PN excitability and contributes to the widely observed negative correlation between complex and simple spike rates. Because they receive input from many CFs, molecular layer interneurons are well positioned to detect the spatiotemporal patterns of CF activity believed to encode error signals. Together, our findings suggest that such inhibition may bind together groups of Purkinje neurons to provide instructive signals to downstream sites in the cerebellar circuit.

Systematic Regional Variations in Purkinje Cell Spiking Patterns

“…Evidence indicates that the pause in SSs is at least partly caused by activation of MLIs and GABA release [46], [50], [73], [74]. However, MLIs appear not to receive climbing fiber synapses [81], but instead are activated by climbing fiber activity via glutamate spillover from climbing fiber-PC synapses [75], [76], [82]. EAAT4 is found in the perisynaptic membrane of climbing fiber-PC synapses [25], [67], and controls glutamate spillover at those synapses [27], [83], raising the possibility that the differing EAAT4 expression levels may also underlie the observed differences in active suppression of SSs between Z+ and Z− bands.…”

Motor Learning and the Cerebellum

“…Enhanced simple spike activity, as observed in the zebrin-negative modules, will lead to reduced firing of these cerebellar nuclei neurons that inhibit the inferior olivary neurons leading to an increase in complex spike activity (De Zeeuw et al 1988). Because an increase in complex spike activity suppresses simple spike frequency through cerebellar cortical interneurons in the molecular layer (Mathews et al 2012;Coddington et al 2013), this network effect ultimately provides an excellent way to mediate homeostasis of activity within the olivocerebellar modules (Fig. 3B,C).…”

The ubiquitous nature of multivesicular release

“…A notable exception is glutamate spillover from the climbing fiber (CF) to MLIs in the cerebellar cortex. Here, high MVR allows glutamate to activate interneuron AMPARs and NMDARs, generating slow and long-lasting excitation [62] that increases firing for tens of milliseconds (see below and [63, 64]).…”