Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine

Abstract

SUMMARY Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine’s ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of Gi-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response.

Striatal synapses, circuits, and Parkinson's disease

“…Interestingly, cocaine-induced locomotion is also diminished in iMSN-Drd2KO mice, but rescued by chemogenetic activation of G i signaling in iSPNs. Although it is not possible to exclude dendritic mechanisms with the approaches used, this work shows that cocaine-induced locomotion is gated by DA modulation of collateral transmission [72]. Consistent with this model, selective deletion of D2R from iSPNs alone increased GABAergic transmission presumably in part at collateral connections, decreased firing of both iSPNs and dSPNs, and caused hypokinesia [73].…”

“…Moreover, it is almost impossible to selectively manipulate collateral synapses without affecting other connections in the striatum. The latter problem was recently circumvented by using a combination of novel genetic, optogenetic and chemogenetic techniques [72,73]. Dobbs et al found that lateral inhibition, evoked by optogenetically activating a cohort of iSPNs, strongly reduced intrinsic excitability of postsynaptic dSPNs in nucleus accumbens.…”

Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling

“…D2Rs are G i coupled receptors known to modulate neurotransmitter release at presynaptic terminals (Adrover et al, 2014; Dobbs, in press). We tested whether acute activation of G i signaling in iMSNs could revert the enhanced GABAergic transmission observed in iMSN-Drd2KO mice back to control levels.…”

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

“…Conceivably, dyskinesia induced by L-DOPA in PD could result from 2 main factors acting concomitantly, i.e., direct pathway "overactivation" via D1 receptors and indirect pathway "overinhibition" via D2 receptors. There are at least 2 mechanisms by which D2-mediated iSPN overinhibition may contribute to LID, (a) a failure to suppress competing movements when specific motor components are selected (2) and (b) a loss of the physiological lateral inhibition exerted by iSPNs onto dSPNs (49,50). A model whereby both dSPNs and iSPNs contribute to LID has important translational implications that will be discussed below.…”