α-Adrenoceptive Dual Modulation of Inhibitory GABAergic Inputs to Purkinje Cells in the Mouse Cerebellum

Abstract

Noradrenaline (NA) modulates synaptic transmission in various sites of the CNS. In the cerebellar cortex, several studies have revealed that NA enhances inhibitory synaptic transmission by β-adrenoceptor–and cyclic AMP–dependent pathways. However, the effects of α-adrenoceptor activation on cerebellar inhibitory neurotransmission have not yet been fully elucidated. Therefore we investigated the effects of the α1- or α2-adrenoceptor agonist on inhibitory postsynaptic currents (IPSCs) recorded from mouse Purkinje cells (PCs). We found that the nonselective α-adrenoceptor agonist 6-fluoro-norepinephrine increased both the frequency and amplitude of spontaneous IPSCs (sIPSCs). This enhancement was mostly mimicked by the selective α1-adrenoceptor agonist phenylephrine (PE). PE also enhanced the amplitude of evoked IPSCs (eIPSCs) and increased the frequency but not the amplitude of miniature IPSCs (mIPSCs). Moreover, PE decreased the paired-pulse ratio of eIPSCs and did not change γ-aminobutyric acid (GABA) receptor sensitivity in PCs. Conversely, the selective α2-adrenoceptor agonist clonidine significantly reduced both the frequency and the amplitude of sIPSCs. Neither eIPSCs nor mIPSCs were affected by clonidine. Furthermore, presynaptic cell-attached recordings showed that spontaneous activity of GABAergic interneurons was enhanced by PE but reduced by clonidine. These results suggest that NA enhances inhibitory neurotransmitter release by α1-adrenoceptors, which are expressed in presynaptic terminals and somatodendritic domains, whereas NA suppresses the excitability of interneurons by α2-adrenoceptors, which are expressed in presynaptic somatodendritic domains. Thus cerebellar α-adrenoceptors play roles in a presynaptic dual modulation of GABAergic inputs from interneurons to PCs, thereby providing a likely mechanism for the fine-tuning of information flow in the cerebellar cortex.