Molecular mechanism underlying facilitation of cerebellar GABA-mediated transmission following activation of monoaminergic afferent fibers

Noradrenaline (NA) and serotonin (5-HT) released by electrical stimulation into the rat cerebellar cortex from afferent input terminals have been shown to elicit long-term facilitation of inhibitory GABAergic transmission between interneurons, basket cells (BCs), and Purkinje cells (PCs). This study aimed to further examine receptor mechanisms underlying the noradrenergic facilitation. Using cerebellar slices cut from neonatal rats and patch-damp recordings, we explored the actions of adrenoceptor agonists and antagonists on GABAergic synapses. GABA-mediated inhibitory postsynaptic currents (IPSCs) were evoked by focal stimulation and recorded from PCs. Application of NA or isoproterenol (ISP), a beta -receptor agonist increased the amplitude of IPSCs and the frequency of miniature IPSCs without affecting postsynaptic GABA receptor sensitivity and mean amplitude of miniature IPSCs. The enhancement by NA of IPSCs was suppressed by a beta (2)-adrenoceptor antagonist, ICI118,551, but not try a beta (1)-adrenoceptor antagonist, CGP20712A, suggesting that the beta (2)-adrenoceptors on BCs mediate the noradrenergic facilitation of GABAergic transmission Then we performed double recordings from BCs and PCs, which showed that the beta -agonist ISP increased the frequencies of the spontaneous spikes in BCs and the spike-triggered IPSCs in PCs. Forskolin mimicked the actions of beta -agonist in enhancing BC spiking and spike-triggered IPSCs in PCs. Furthermore voltage-clamp experiments showed that BCs exhibit profound activity of a hyperpolarization-activated cation channel current, I-h and that ISP and forskolin enhanced persistent activation of I-h channel. NA and ISP induced BC depolarization which was abolished by the I-h inhibitor ZD7288. Taken together, our data suggest that beta -adrenoceptor-mediated acceleration of I-h, in BCs is involved, at least in part, in noradrenergic facilitation of GABAergic transmission at BC-PC inhibitory synapses.