GABAB Receptors Augment TRPC3-Mediated Slow Excitatory Postsynaptic Current to Regulate Cerebellar Purkinje Neuron Response to Type-1 Metabotropic Glutamate Receptor Activation.

Jinbin Tian,Michael Zhu

doi:10.3390/cells7080090

Abstract

During strong parallel fiber stimulation, glutamate released at parallel fiber-Purkinje cell synapses activates type-1 metabotropic glutamate receptor (mGluR1) to trigger a slow excitatory postsynaptic current (sEPSC) in cerebellar Purkinje neurons. The sEPSC is mediated by transient receptor potential canonical 3 (TRPC3) channels. Often co-localized with mGluR1 in Purkinje neuron dendrites are type B γ-aminobutyric acid receptors (GABABRs) that respond to inhibitory synaptic inputs from interneurons located in the molecular layer of cerebellar cortex. It has been shown that activation of postsynaptic GABABRs potentiates mGluR1 activation-evoked sEPSC in Purkinje cells, but the underlying molecular mechanism remains elusive. Here we report that the augmentation of mGluR1-sEPSC by GABABR activation in Purkinje neurons is completely absent in TRPC3 knockout mice, but totally intact in TRPC1-, TRPC4-, and TRPC1,4,5,6-knockout mice, suggesting that TRPC3 is the only TRPC isoform that mediates the potentiation. Moreover, our results indicate that the potentiation reflects a postsynaptic mechanism that requires both GABABRs and mGluR1 because it is unaffected by blocking neurotransmission with tetrodotoxin but blocked by inhibiting either GABABRs or mGluR1. Furthermore, we show that the co-stimulation of GABABRs has an effect on shaping the response of Purkinje cell firing to mGluR1-sEPSC, revealing a new function of inhibitory input on excitatory neurotransmission. We conclude that postsynaptic GABABRs regulate Purkinje cell responses to strong glutamatergic stimulation through modulation of mGluR1-TRPC3 coupling. Since mGluR1-TRPC3 coupling is essential in cerebellar long-term depression, synapse elimination, and motor coordination, our findings may have implications in essential cerebellar functions, such as motor coordination and learning.

Highlights

Purkinje cells in the cerebellum serve vital functions in motor coordination and motor learning.These neurons receive glutamatergic inputs at their extremely elaborated dendrites from parallel fibers at the molecular layer of cerebellar cortex and send outputs to deep cerebellar nuclei in the form of γ-aminobutyric acid (GABA) [1,2]
We found that GABAB R activation still converges on mGluR1-transient receptor potential canonical 3 (TRPC3) coupling to augment slow excitatorypostsynaptic postsynaptic current (EPSC) (sEPSC) and this modulation helps shape the Purkinje cell firing response to mGluR1 activation
Previous studies have shown the critical involvement of TRPC3 in mediating sEPSC of cerebellar

Summary

Introduction

Purkinje cells in the cerebellum serve vital functions in motor coordination and motor learning These neurons receive glutamatergic inputs at their extremely elaborated dendrites from parallel fibers at the molecular layer of cerebellar cortex and send outputs to deep cerebellar nuclei in the form of γ-aminobutyric acid (GABA) [1,2]. Cells 2018, 7, 90 input, which in experimental settings requires multiple pulses of high intensity and high frequency electrical stimulations of the parallel fibers [3,5] This reflects high levels of glutamate release at the parallel fiber-Purkinje cell synapses, causing a spillover of the neurotransmitter from the synaptic clefts to activate mGluR1 abundantly present at the extra-postsynaptic sites of these synapses [6]. The mGluR1-mediated signaling is essential for synaptic plasticity of Purkinje cells, such as cerebellar long-term depression (LTD), the long-lasting reduction of transmission efficiency at the parallel fiber-Purkinje cell synapses [9]

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