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The Journal of Neuroscience, March 21, 2007, 27(12):3148-3156; doi:10.1523/JNEUROSCI.5535-06.2007

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Behavioral/Systems/Cognitive
Involvement of I_h in Dopamine Modulation of Tonic Firing in Striatal Cholinergic Interneurons

Ping Deng, Yuchun Zhang, and Zao C. Xu

Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202

Correspondence should be addressed to Dr. Ping Deng, Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS 507, Indianapolis, IN 46202. Email: pideng{at}iupui.edu

Striatal cholinergic interneurons are tonically active neurons and respond to sensory stimuli by transiently suppressing firing that is associated with sensorimotor learning. The pause in tonic firing is dependent on dopaminergic activity; however, its cellular mechanisms remain unclear. Here, we report evidence that dopaminergic inhibition of hyperpolarization-activated cation current (I_h) is involved in this process. In neurons exhibiting regular firing in vitro, exogenous application of dopamine caused a prolongation of the depolarization-induced pause and an increase in the duration of slow afterhyperpolarization (sAHP) after depolarization. Partially blocking I_h with specific blocker ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride) reduced firing and mimicked the effects of dopamine on sAHP. The I_h, being active at membrane potentials negative than –50 mV, was inhibited by dopamine via activation of the D₂-like receptor, but not D₁-like receptor. The inhibitory effects of the D₂ receptor activation on I_h were mediated through a protein kinase A-independent cyclic AMP pathway. Consistently, D₂-like receptor agonist quinpirole showed comparable effects on sAHP and firing rate as those induced by I_h channel blocker. Moreover, dopamine was unable to further affect the sAHP duration in neurons when I_h was blocked. These findings indicate that D₂ receptor-dependent inhibition of I_h may be a novel mechanism for modulating the pause response in tonic firing in cholinergic interneurons.

Key words: hyperpolarization-activated cation current; afterhyperpolarization; pause; dopamine; ZD7288; basal ganglia

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Received Dec. 21, 2006; revised Feb. 9, 2007; accepted Feb. 15, 2007.

Correspondence should be addressed to Dr. Ping Deng, Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS 507, Indianapolis, IN 46202. Email: pideng{at}iupui.edu

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