The Journal of Neurophysiology Vol. 85 No. 5 May 2001, pp. 1847-1857
Copyright ©2001 by the American Physiological Society

Synaptically Released Neurotransmitter Fails to Desensitize Postsynaptic GABA_A Receptors in Cerebellar Cultures

Neurobiology Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom

Mellor, J. R. and A. D. Randall. Synaptically Released Neurotransmitter Fails to Desensitize Postsynaptic GABA_A Receptors in Cerebellar Cultures. J. Neurophysiol. 85: 1847-1857, 2001. GABA concentration jump experiments performed on membrane patches predict that postsynaptic GABA_A receptors will become desensitized following the release of the contents of a single GABA-containing synaptic vesicle. To examine this we used a single synaptic bouton stimulation technique to directly examine whether postsynaptic GABA_A receptors in cultured cerebellar granule cells exhibit transmitter-induced desensitization. In a large number of recordings, no evidence was found for desensitization of postsynaptic GABA_A receptors by vesicularly released transmitter. This was the case even when as many as 40 vesicles were released from a single bouton within 1.5 s. In addition, postsynaptic depolarization and application of the benzodiazepine flunitrazepam, manipulations previously shown to enhance desensitization of GABA_A receptors, failed to unmask transmitter-induced desensitization. In contrast, a single 2- to 3-s application of a high concentration of exogenous GABA was able to depress synaptic responsiveness for up to 70 s. Furthermore, pharmacological depletion of GABA eliminated inhibitory synaptic communication, suggesting that GABA is the transmitter and the desensitization-resistant inhibitory postsynaptic currents are not mediated by a "nondesensitizing" ligand such as -alanine. Overall our data indicate that a specific desensitization-resistant population of GABA_A receptors are present at postsynaptic sites on cultured cerebellar granule cells.