Excitability increase induced by beta-adrenergic receptor-mediated activation of hyperpolarization-activated cation channels in rat cerebellar basket cells.

In the preceding paper, we showed that norepinephrine (NE) enhances the spontaneous spike firings in cerebellar interneurons, basket cells (BCs), resulting in an increase in the frequency of BC-spike-triggered inhibitory postsynaptic currents (IPSCs) in Purkinje cells (PCs), and that the effects of NE on GABAergic BCs are mediated by beta(2)-adrenergic receptors. This study aimed to further examine the ionic mechanism underlying the beta-adrenoceptor-mediated facilitation of GABAergic transmission at the BC-PC synapses. Using cerebellar slices obtained from 15- to 21-day-old rats and whole cell recordings, we investigated ionic currents in the BCs and the effects of the beta-agonist isoproterenol (ISP) as well as forskolin on the BC excitability. Hyperpolarizing voltage steps from a holding potential of -50 mV elicited a hyperpolarization-activated inward current, I(h), in the BC. This current exhibited voltage-dependent activation that was accelerated by strong hyperpolarization, displaying two time constants, 84 +/- 6 and 310 +/- 40 ms, at -100 mV, and was inhibited by 20 microM ZD7288. ISP and forskolin, both at 20 microM, enhanced I(h) by shifting the activation curve by 5.9 and 9.3 mV toward positive voltages, respectively. Under the current-clamp mode, ISP produced a depolarization of 7 +/- 3 mV in BCs and reduced their input resistance to 74 +/- 6%. ISP and a cAMP analogue, Rp-cAMP-S, increased the frequency of spontaneous spikes recorded from BCs using the cell-attached mode. The I(h) inhibitor ZD7288 decreased the BC spike frequency and abolished the ISP-induced increase in spike discharges. The results suggest that NE depolarizes the BCs through beta-adrenoceptor-mediated cAMP formation linking it to activation of I(h), which is, at least in part, involved in noradrenergic afferent-mediated facilitation of GABAergic synaptic activity at BC-PC connections in the rat cerebellum.