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1 Department of Pharmacology, Nippon Medical School, Tokyo 113-8602, Japan
2 Waseda-Olympus Bioscience Research Institute, Helios, no. 05-01/02, 11 Biopolis Way, Singapore 138667
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 ß-adrenoceptor activation. Stimulation of ß-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 ß-adrenoceptor-mediated acceleration of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel. Furthermore, the ß-adrenoceptor- and protein kinase A-mediated LTP was triggered by enhancement of the Ca2+ sensitivity of the release machinery and increase in the readily releasable pool. ß-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 ß-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.
(Received 2 February 2005;
accepted after revision 22 March 2005;
first published online 24 March 2005)
Corresponding author S. Konishi: Waseda-Olympus Bioscience Research Institute, Helios, no. 05-01/02, 11 Biopolis Way, Singapore 138667. Email: skonishi{at}waseda.jp
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