Dopamine-Deprived Striatal GABAergic Interneurons Burst and Generate Repetitive Gigantic IPSCs in Medium Spiny Neurons

Abstract

Striatal GABAergic microcircuits modulate cortical responses and movement execution in part by controlling the activity of medium spiny neurons (MSNs). How this is altered by chronic dopamine depletion, such as in Parkinson's disease, is not presently understood. We now report that, in dopamine-depleted slices of the striatum, MSNs generate giant spontaneous postsynaptic GABAergic currents (single or in bursts at 60 Hz) interspersed with silent episodes, rather than the continuous, low-frequency GABAergic drive (5 Hz) observed in control MSNs. This shift was observed in one-half of the MSN population, including both "D 1 -negative" and "D 1 -positive" MSNs. Single GABA and NMDA channel recordings revealed that the resting membrane potential and reversal potential of GABA were similar in control and dopamine-depleted MSNs, and depolarizing, but not excitatory, actions of GABA were observed. Glutamatergic and cholinergic antagonists did not block the GABAergic oscillations, suggesting that they were generated by GABAergic neurons. In support of this, cell-attached recordings revealed that a subpopulation of intrastriatal GABAergic interneurons generated bursts of spikes in dopamine-deprived conditions. This subpopulation included low-threshold spike interneurons but not fast-spiking interneurons, cholinergic interneurons, or MSNs. Therefore, a population of local GABAergic interneurons shifts from tonic to oscillatory mode when dopamine deprived and gives rise to spontaneous repetitive giant GABAergic currents in one-half the MSNs. We suggest that this may in turn alter integration of cortical signals by MSNs.

Upregulation of D2-class signaling in dopamine-denervated striatum is in part mediated by D3receptors acting on CaV2.1 channels via PIP2depletion

“…However, after DA depletion, high affinity and supersensitivity of D 3 R in the presence of very low DA concentrations may greatly decrease inhibition among striatal MSNs (Taverna et al 2008;Tecuapetla et al 2007), thus impairing microcircuit dynamics (Carrillo-Reid et al 2008). In contrast, a subpopulation of low threshold spike (LTS) interneurons greatly increase their inhibitory output after DA depletion, eliciting sudden episodes of giant inhibitory synaptic potentials (Dehorter et al 2009). Coincident with these circuit events in monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a partial agonist of D 3 R, induces a reduction in dyskinesias, perhaps by controlling LTS output, and at the same time stops interfering with L-dihydroxyphenylalanine (L-DOPA) therapeutic Fig.…”

CaMKII Activity in the Ventral Tegmental Area Gates Cocaine-Induced Synaptic Plasticity in the Nucleus Accumbens

“…One day after the CPP test, the rats were euthanized and living NAc slices were prepared. Whole-cell voltage-clamp recordings were made from MSNs of the NAc shell at a holding potential of À 80 mV, near the resting membrane potential of these neurons (Dehorter et al, 2009). MSNs are GABAergic neurons that make up the vast majority (90-95%) of cells in the NAc (Meredith, 1999;Zhou et al, 2002).…”

Functional roles of neurotransmitters and neuromodulators in the dorsal striatum

“…Although SOM-positive GABAergic terminals have been observed on the dendrites of MSNs (Kubota and Kawaguchi 2000), it has been difficult to explain their functional role. Interestingly, under dopamine depletion states, GABAergic inhibition onto MSNs by LTS interneurons was shown to become potentiated (Dehorter et al 2009). This distinct set of neurons is thought to modulate striatal circuits by releasing neuromodulators such as NPY, SOM, and NO in a spatial and temporal manner rather than as a fast synaptic transmission (O'Donnell and Grace 1997; West and Grace 2004;Galarraga et al 2007).…”