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The Journal of Neuroscience, November 14, 2007, 27(46):12452-12463; doi:10.1523/JNEUROSCI.3413-07.2007

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Cellular/Molecular
Enhancement of GABA Release through Endogenous Activation of Axonal GABA_A Receptors in Juvenile Cerebellum

Federico F. Trigo, Mireille Chat, and Alain Marty

Laboratoire de Physiologie Cérébrale, Centre National de la Recherche Scientifique and Université Paris Descartes, 75006 Paris, France

Correspondence should be addressed to Alain Marty, Laboratoire de Physiologie Cérébrale, Centre National de la Recherche Scientifique and Université Paris Descartes, 45 rue des Saints Pères, 75006 Paris, France. Email: alain.marty{at}univ-paris5.fr

Recent evidence indicates the presence of presynaptic GABA_A receptors (GABA_ARs) in the axon domain of several classes of central neurons, including cerebellar basket and stellate cells. Here, we investigate the possibility that these receptors could be activated in the absence of electrical or chemical stimulation. We find that low concentrations of GABA increase the frequency of miniature GABAergic synaptic currents. Submaximal concentrations of a GABA_AR blocker, gabazine, decrease both the miniature current frequency and the probability of evoked GABA release. Zolpidem, an agonist of the benzodiazepine binding site, and NO-711 (1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride), a blocker of GABA uptake, both increase the frequency of miniature currents. These effects occur up to postnatal day 14, but not later. Immunohistochemistry indicates the presence of 1-containing GABA_ARs in interneuron presynaptic terminals with a similar age dependence. We conclude that, under resting conditions, axonal GABA_ARs are significantly activated, that this activation results in enhanced GABA release, and that it can be augmented by increasing the affinity of GABA_ARs or reducing GABA uptake. Our findings suggest the existence of a positive-feedback mechanism involving presynaptic GABA_ARs that maintains a high release rate and a high local GABA concentration in the immature cerebellar network.

Key words: cerebellum; GABA; GABA_A receptor; presynaptic receptor; synaptic terminal; molecular layer interneuron

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Received May 25, 2007; revised Sept. 10, 2007; accepted Sept. 17, 2007.

Correspondence should be addressed to Alain Marty, Laboratoire de Physiologie Cérébrale, Centre National de la Recherche Scientifique and Université Paris Descartes, 45 rue des Saints Pères, 75006 Paris, France. Email: alain.marty{at}univ-paris5.fr

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				P. Long, A. Mercer, R. Begum, G. J. Stephens, T. S. Sihra, and J. N. Jovanovic Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release J. Biol. Chem., March 27, 2009; 284(13): 8726 - 8737. [Abstract] [Full Text] [PDF]

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