β-Adrenoceptor-mediated long-term up-regulation of the release machinery at rat cerebellar GABAergic synapses

Properly regulated interactions among excitatory and inhibitory synapses are critical for brain function. Compared to excitatory synapses, much less is known about the gain control mechanisms at inhibitory synapses. Herein we report a mechanism of noradrenergic long-term potentiation (LTP) at inhibitory synapses following presynaptic beta-adrenoceptor activation. Stimulation of beta-adrenoceptors elicited LTP of GABA release from terminals of cerebellar interneurones. This action was dependent on the cAMP/protein kinase A signalling cascade and independent of the beta-adrenoceptor-mediated acceleration of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel. Furthermore, the beta-adrenoceptor- and protein kinase A-mediated UP was triggered by enhancement of the Ca2+ sensitivity of the release machinery and increase in the readily releasable pool. beta-Adrenoceptor activation also accelerated the recruitment of GABA into the releasable pool and enhanced synchronous and asynchronous release of GABA from the presynaptic terminal. Thus, the up-regulation of GABA release machinery mediated by noradrenaline and beta-adrenoceptor activation provides a likely mechanism of feedforward inhibition of the cerebellar output neurone Purkinje cell, leading to a profound effect on motor control and learning associated with the cerebellum.