Differential GABAergic and Glycinergic Inputs of Inhibitory Interneurons and Purkinje Cells to Principal Cells of the Cerebellar Nuclei

Abstract

The principal neurons of the cerebellar nuclei (CN), the sole output of the olivo-cerebellar system, receive a massive inhibitory input from Purkinje cells (PCs) of the cerebellar cortex. Morphological evidence suggests that CN principal cells are also contacted by inhibitory interneurons, but the properties of this connection are unknown. Using transgenic, tracing, and immunohistochemical approaches in mice, we show that CN interneurons form a large heterogeneous population with GABA/glycinergic phenotypes, distinct from GABAergic olive-projecting neurons. CN interneurons are found to contact principal output neurons, via glycine receptor (GlyR)-enriched synapses, virtually devoid of the main GABA receptor (GABAR) subunits ␣1 and ␥2. Those clusters account for 5% of the total number of inhibitory receptor clusters on principal neurons. Brief optogenetic stimulations of CN interneurons, through selective expression of channelrhodopsin 2 after viral-mediated transfection of the flexed gene in GlyT2-Cre transgenic mice, evoked fast IPSCs in principal cells. GlyR activation accounted for 15% of interneuron IPSC amplitude, while the remaining current was mediated by activation of GABAR. Surprisingly, small GlyR clusters were also found at PC synapses onto principal CN neurons in addition to ␣1 and ␥2 GABAR subunits. However, GlyR activation was found to account for Ͻ3% of the PC inhibitory synaptic currents evoked by electrical stimulation. This work establishes CN glycinergic neurons as a significant source of inhibition to CN principal cells, forming contacts molecularly distinct from, but functionally similar to, Purkinje cell synapses. Their impact on CN output, motor learning, and motor execution deserves further investigation.

Dopamine D1 Receptor–Positive Neurons in the Lateral Nucleus of the Cerebellum Contribute to Cognitive Behavior

“…Different cell types within the LCN have distinct electrophysiological profiles(32, 36, 37, 40, 41). To characterize the electrophysiological properties of D1R neurons, we performed whole-cell patch clamp recordings on fluorescently identified neurons from acute cerebellar slices.…”

Selective Modulation of Histaminergic Inputs on Projection Neurons of Cerebellum Rapidly Promotes Motor Coordination via HCN Channels

“…Interestingly, histamine H2 receptors, mediating the histamine-induced excitation on projection neurons, are only expressed in glutamatergic and glycinergic neurons (only in the ventral and intermediate part of FN) rather than GABAergic and GABA/glycinergic ones. Since glutamatergic and glycinergic neurons are principle projection neurons in the cerebellar nuclei, whereas GABAergic and GABA/glycinergic ones are nucleo-olivary neurons and interneurons [16,42], the differential expression of the H2 receptors accounts for why histamine exerts a selective action on projection neurons, but not interneurons in the cerebellar nuclei.…”

Cerebellar premotor output neurons collateralize to innervate the cerebellar cortex

“…A pathway from the CbN to the granule cell layer has been identified, but a systematic examination of collaterals of premotor CbN principle neurons, thus constituting a corollary discharge pathway, had not been performed. The cerebellar nuclei contain at least three cell types: glutamatergic premotor principle output neurons, GABAergic and glycinergic interneurons, and GABAergic nucleo-olivary neurons (Chan-Palay, 1977; Uusisaari and Knöpfel, 2010; Husson et al, 2014). This cellular diversity underlines the importance of isolating specific nucleocortical populations for examination.…”