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

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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.