Distinct Mechanisms of CB1 and GABA Receptor Presynaptic Modulation of Striatal Indirect Pathway Projections to Mouse Globus Pallidus

Overview

Journal J Physiol

Specialty Physiology

Date 2022 Nov 22

PMID 36412169

Authors

Giacomo Sitzia

Karina Possa Abrahao

Daniel Liput

Gian Marco Calandra

David M Lovinger

Affiliations

Soon will be listed here.

Abstract

Presynaptic modulation is a fundamental process regulating synaptic transmission. Striatal indirect pathway projections originate from A2A-expressing spiny projection neurons (iSPNs), targeting the globus pallidus external segment (GPe) and control the firing of the tonically active GPe neurons via GABA release. It is unclear if and how the presynaptic G-protein-coupled receptors (GPCRs), GABA and CB1 receptors modulate iSPN-GPe projections. Here we used an optogenetic platform to study presynaptic Ca and GABAergic transmission at iSPN projections, using a genetic strategy to express the calcium sensor GCaMP6f or the excitatory channelrhodopsin (hChR2) on iSPNs. We found that P/Q-type calcium channels are the primary voltage-gated Ca channel (VGCC) subtype controlling presynaptic calcium and GABA release at iSPN-GPe projections. N-type and L-type VGCCs also contribute to GABA release at iSPN-GPe synapses. GABA receptor activation resulted in a reversible inhibition of presynaptic Ca transients (PreCaTs) and an inhibition of GABAergic transmission at iSPN-GPe synapses. CB1 receptor activation did not inhibit PreCaTs but inhibited GABAergic transmission at iSPN-GPe projections. CB1 effects on GABAergic transmission persisted in experiments where Na and K 1 were blocked, indicating a VGCC- and K 1-independent presynaptic mechanism of action of CB1 receptors. Taken together, presynaptic modulation of iSPN-GPe projections by CB1 and GABA receptors is mediated by distinct mechanisms. KEY POINTS: P/Q-type are the predominant voltage-gated Ca channels controlling presynaptic Ca and GABA release on the striatal indirect pathway projections. GABA receptors modulate iSPN-GPe projections via a VGCC-dependent mechanism. CB1 receptors modulate iSPN-GPe projections via a VGCC-independent mechanism.

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