Involvement of I(h) in dopamine modulation of tonic firing in striatal cholinergic interneurons

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.