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

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, GABABand CB1 receptors, modulate iSPN-GPe 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 synapses. GABABreceptor 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 transmission at iSPN-GPe projections. CB1 effects on GABAergic transmission persisted in experiments where NaVand 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 GABABreceptors is mediated by distinct mechanisms.Key PointsP/Q-type are the predominant VGCC controlling presynaptic Ca2+and GABA release on the striatal indirect pathway projectionsGABABreceptor modulate of iSPN-GPe projections via a VGCC- dependent mechanismCB1 receptors modulate iSPN-GPe projections via a VGCC- independent mechanism