Developmental α2-adrenergic regulation of noradrenergic synaptic facilitation at cerebellar GABAergic synapses

- NA induced the long-lasting facilitation of sIPSCs until the second postnatal week.
- NA facilitated sIPSCs through the synergistic effects of α1- and β-AR-activation.
- The α1- and β-AR-mediated synergistic effect required ERK1/2 activation.
- α2-AR activation suppressed the NA-mediated long-lasting facilitation of sIPSCs.
- NA could serve as a neurotropic factor to strengthen GABAergic synaptic transmission.

In the central nervous system, the normal development of neuronal circuits requires adequate temporal activation of receptors for individual neurotransmitters. Previous studies have demonstrated that α2-adrenoceptor (α2-AR) activation eliminates spontaneous action potentials of interneurons in the cerebellar molecular layer (MLIs) and subsequently reduces the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in Purkinje cells (PCs) after the second postnatal week. The magnitude of the α2-adrenergic reduction in sIPSC frequency is enhanced during the third postnatal week because of an increase in firing-derived sIPSCs. However, little is known about the effects of α2-AR activation by noradrenaline (NA) on cerebellar GABAergic synaptic transmission that is accompanied by the activation of other AR subtypes, α1- and β-ARs. Here, we developmentally examined the roles of α2-AR activation in the noradrenergic facilitation of sIPSCs in cerebellar PCs. Until the second postnatal week, when substantial inhibitory effects of α2-ARs are absent, NA potentiated sIPSCs and maintained the increased sIPSC frequency, suggesting that NA causes long-lasting facilitation of GABAergic synaptic transmission through α1- and β-AR activation. After the second postnatal week, NA transiently increased the sIPSC frequency, whereas blocking α2-ARs sustained the noradrenergic sIPSC facilitation and increase in the firing rate of MLIs, suggesting that α2-AR activation suppresses the noradrenergic facilitation of GABAergic synaptic transmission. The simultaneous activation of α1- and β-ARs by their specific agonists mimicked the persistent facilitation of sIPSC frequency, which required extracellular signal-regulated kinase 1/2 activation. These findings indicate that NA acts as a neurotrophic factor that strengthens GABAergic synaptic transmission in the developing cerebellar cortex and that α2-ARs temporally restrain the noradrenergic facilitation of sIPSCs after GABAergic synaptogenesis.