Increased GABAergic transmission in neuropeptide Y-expressing neurons in the dopamine-depleted murine striatum.

As the main input nucleus of the basal ganglia, the striatum plays a central role in planning, control, and execution of movement and motor skill learning. More than 90% of striatal neurons, so-called medium spiny neurons (MSN), are GABAergic projection neurons, innervating primarily the substantia nigra pars reticulata or the globus pallidus internus. Remaining are GABAergic and cholinergic interneurons, synchronizing and controlling striatal output by reciprocal connections with MSN. Besides prominent local cholinergic influence, striatal function is globally regulated by dopamine (DA) from the nigrostriatal pathway. Little is known whether DA depletion, as occurs in Parkinson's disease (PD), affects the activity of striatal interneurons. Here, we focused on neuropeptide Y-expressing interneurons, which are among the major subgroups of GABAergic interneurons in the striatum. We investigated the effects of striatal DA depletion on GABAergic transmission in NPY interneurons by electrophysiologically recording GABAergic spontaneous (sIPSC) and miniature IPSCs (mIPSC) in identified NPY interneurons in slices from 6-OHDA- and vehicle-injected transgenic NPY-hrGFP mice using the whole cell patch-clamp technique. We report a significant increase in sIPSC and mIPSC frequency, as well as the occurrence of giant synaptic and burst sIPSCs in the 6-OHDA group, suggesting changes in GABAergic circuit activity and synaptic transmission. IPSC kinetics remained unchanged, pointing to mainly presynaptic changes in GABAergic transmission. These results show that chronic DA depletion following 6-OHDA injection causes an activity-dependent and -independent increase of synaptic GABAergic inhibition onto striatal NPY interneurons, confirming their involvement in the functional impairments of the DA-depleted striatum.