D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons
Por:
Maurice N., Mercer J., Chan C.S., Hernandez-Lopez S., Held J., Tkatch T., Surmeier D.J.
Publicada:
1 ene 2004
Resumen:
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, D 2 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.
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