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The Journal of Neuroscience, November 17, 2004, 24(46):10289-10301; doi:10.1523/JNEUROSCI.2155-04.2004

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Cellular/Molecular
D₂ Dopamine Receptor-Mediated Modulation of Voltage-Dependent Na⁺ Channels Reduces Autonomous Activity in Striatal Cholinergic Interneurons

Nicolas Maurice, Jeff Mercer, C. Savio Chan, Salvador Hernandez-Lopez, Joshua Held, Tatiana Tkatch, and D. James Surmeier

Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

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 D₂ dopamine receptor modulation of Na⁺ 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, D₂ receptor stimulation in tissue slices reduced the autonomous spiking in the presence of synaptic blockers. Second, in acutely isolated neurons, D₂ receptor activation led to a reduction in Na⁺ 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 D₂ receptor agonists on pacemaking. Fourth, simulation of cholinergic interneuron pacemaking revealed that a modest increase in the entry of Na⁺ channels into the slow-inactivated 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.

Key words: sodium channel; dopamine; striatum; scRT-PCR; neuromodulation; voltage clamp; slice; Parkinson's disease

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Received Oct 24, 2003; revised September 17, 2004; accepted September 17, 2004.

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