Cholinergic interneuron control of GABAergic circuits targeting spiny projection neurons is disrupted in parkinsonian models

Parkinson’s disease (PD) is known to alter the intrinsic properties of striatal cholinergic interneurons (ChIs). However, how PD shapes ChI control of intrastriatal GABAergic circuits regulating principal spiny projection neurons (SPNs) is unknown. To fill this gap, striatal circuits in healthy and parkinsonian mice were interrogated. In ex vivo brain slices from healthy mice, optogenetic stimulation of ChIs evoked GABA _A receptor currents in both indirect and direct pathway SPNs that were attributable to nicotinic acetylcholine receptor (nAChR)-mediated activation of GABAergic interneurons (GIs). Simulations suggested that this circuit exerts a state-dependent control of SPN dendritic integration that was modulated by concomitant muscarinic receptor signaling. Surprisingly, in mouse models of prodromal and parkinsonian states, the ability of ChIs to engage this intrastriatal circuitry was disrupted because interneurons down-regulated nicotinic AChRs. Taken together, these studies suggest that impaired ChI control of GABAergic interneurons contributes to behavioral deficits in both prodromal and clinical PD states.