Distinct mechanisms of CB1 and GABA_Breceptor presynaptic modulation of striatal indirect pathway projections to mouse Globus Pallidus

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 GPCRs, GABAB and CB1 receptors, modulate iSPN projections. Here we used an optogenetic platform to study presynaptic Ca2+ 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 VGCC-subtype controlling presynaptic calcium and GABA release at iSPN-GPe projections. N-type and L-type VGCCs contribute to GABA release at iSPN-GPe projections. GABAB receptor activation resulted in a reversible inhibition of presynaptic Ca2+ transients (PreCaTs) and an inhibition of GABAergic transmission at iSPN-GPe synapses. CB1 receptor activation did not inhibit PreCaTs while inhibiting GABAergic oIPSCs at iSPN-GPe synapses. CB1 effects on GABAergic transmission persisted in experiments where NaV and KV1 were blocked, indicating a VGCC- and KV1 independent presynaptic mechanism of action of CB1 receptors. Taken together, presynaptic modulation of iSPN-GPe projections by CB1 and GABAB receptors is mediated by distinct mechanisms.

A non-canonical striatopallidal “Go” pathway that supports motor control

“…We also wondered if and to what extent GPe terminals receive a copy of the same neuronal information sent by dSPNs to SNr terminals. Indeed, existing work points to a highly correlated but possible dissociation of activity between soma and presynaptic terminals in various systems [30][31][32][33] and to the existence of multiple mechanisms for local regulation of presynaptic calcium levels 34,35 . In this respect, the degree to which the activity of presynaptic terminals from two different axonal outputs correlates vs. dissociates has not been addressed.…”