Alpha-adrenoceptive dual modulation of inhibitory GABAergic inputs to Purkinje cells in the mouse cerebellum

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 beta-adrenoceptor-and cyclic AMP-dependent pathways. However, the effects of alpha-adrenoceptor activation on cerebellar inhibitory neurotransmission have not yet been fully elucidated. Therefore we investigated the effects of the alpha1- or alpha2-adrenoceptor agonist on inhibitory postsynaptic currents (IPSCs) recorded from mouse Purkinje cells (PCs). We found that the nonselective alpha-adrenoceptor agonist 6-fluoro-norepinephrine increased both the frequency and amplitude of spontaneous IPSCs (sIPSCs). This enhancement was mostly mimicked by the selective alpha1-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 gamma-aminobutyric acid (GABA) receptor sensitivity in PCs. Conversely, the selective alpha2-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 alpha1-adrenoceptors, which are expressed in presynaptic terminals and somatodendritic domains, whereas NA suppresses the excitability of interneurons by alpha2-adrenoceptors, which are expressed in presynaptic somatodendritic domains. Thus cerebellar alpha-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.