D₂Dopamine Receptor-Mediated Modulation of Voltage-Dependent Na⁺Channels Reduces Autonomous Activity in Striatal Cholinergic Interneurons

Abstract

Striatal cholinergic interneurons are critical elements of the striatal circuitry controlling motor planning, movement, and associative learning. Intrastriatal release of dopamine and inhibition of interneuron activity is thought to be a critical link between behaviorally relevant events, such as reward, and alterations in striatal function. However, the mechanisms mediating this modulation are unclear. Using a combination of electrophysiological, molecular, and computational approaches, the studies reported here show that D 2 dopamine receptor modulation of Na ϩ currents underlying autonomous spiking contributes to a slowing of discharge rate, such as that seen in vivo. Four lines of evidence support this conclusion. First, D 2 receptor stimulation in tissue slices reduced the autonomous spiking in the presence of synaptic blockers. Second, in acutely isolated neurons, D 2 receptor activation led to a reduction in Na ϩ currents underlying pacemaking. The modulation was mediated by a protein kinase C-dependent enhancement of channel entry into a slow-inactivated state at depolarized potentials. Third, the sodium channel blocker TTX mimicked the effects of D 2 receptor agonists on pacemaking. Fourth, simulation of cholinergic interneuron pacemaking revealed that a modest increase in the entry of Na ϩ channels into the slowinactivated state was sufficient to account for the slowing of pacemaker discharge. These studies establish a cellular mechanism linking dopamine and the reduction in striatal cholinergic interneuron activity seen in the initial stages of associative learning.

Loss of Muscarinic Autoreceptor Function Impairs Long-Term Depression But Not Long-Term Potentiation in the Striatum

“…Our data are consistent with the novel concept that bidirectional synaptic plasticity in the striatum is strictly regulated by ACh provided by ChIs. Under physiological conditions, striatal dopamine inhibits the activity of ChIs and ACh release (DeBoer et al, 1996;Pisani et al, 2000;Maurice et al, 2004). Moreover, different pathophysiological conditions characterized by striatal dopaminergic dysfunction, including Parkinson's disease and dystonia, are accompanied by abnormal cholinergic function Pisani et al, 2007).…”

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

“…Dopaminergic inputs to the ventral striatum arise from the ventral tegmentum (VTA) and substantia nigra (SN), which themselves are recipients of cholinergic projections from PM neurons. Activation of a variety of pre-and postsynaptic dopamine receptors strongly regulates the release of ACh and the excitability of striatal cholinergic interneurons (Maurice et al, 2004;Wang et al, 2006). In addition, local circuits of opiate peptide and GABAergic neurons influence the net levels of striatal cholinergic tone.…”

“…2). Changes in the activity profile of striatal TANS, referred to as "pauses," are thought to arise in part from the slowing of autonomous pacemaker activity and in part to local changes in dopamine, glutamate, and GABA signaling (Cragg, 2006;Maurice et al, 2004;Wang et al, 2006). The association between changes in striatal cholinergic "tone" and salience/reward prediction has continued to stoke the fire of physiologists' interests in the workings of striatal ACh circuits (see Cragg, 2006 for review;Apicella, 2002;Maurice et al, 2004;Wang et al, 2006 for recent highlights).…”

“…But new results reveal that depending on the type and location of the dopaminergic and muscarinic receptors activated, the net effect may be to stably enhance or depress the activity of the GABAergic MSpNs (Cragg, 2006;Wang et al, 2006;Wilson, 2006;). Indeed, the potential for mutual tuning of TANS and DANS seems more than flexible enough to account for the differences in valence and timing of all of the synaptic changes observed in striatum (Calabresi et al, 2000;Cragg, 2006;Maurice et al, 2004;Wang et al, 2006).…”

Endogenous Serotonin Excites Striatal Cholinergic Interneurons via the Activation of 5-HT 2C, 5-HT6, and 5-HT7 Serotonin Receptors: Implications for Extrapyramidal Side Effects of Serotonin Reuptake Inhibitors

“…They are also recipient of a crucial dopaminergic innervation from the substantia nigra pars compacta, and of GABAergic afferents from striatal interneurons. Each of these transmitters has been shown to profoundly modulate both the intrinsic excitability and the synaptic efficacy and plasticity of these interneurons Aosaki et al, 1998;Suzuki et al, 2001;Pisani et al, 2000;Bonsi et al, 2004Bonsi et al, , 2005Maurice et al, 2004).…”