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The Journal of Neuroscience, November 19, 2003, 23(33):10475-10486

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Cellular/Molecular
Regulation of Exocytosis from Single Visualized GABAergic Boutons in Hippocampal Slices

Darrin H. Brager,¹ Paul W. Luther,^1,2 Ferenc Erdélyi,³ Gabor Szabó,³ and Bradley E. Alger^1,4

¹Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, ²Department of Molecular Biology and Biophysics, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, ³Department of Gene Technology and Developmental Neuroscience, Institute of Experimental Medicine, H-1450, Budapest, Hungary, and ⁴Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201

Regulation of GABA release is crucial for normal brain functioning, and GABA_A-mediated IPSCs are strongly influenced by repetitive stimulation and neuromodulation. However, GABA exocytosis has not been examined directly in organized tissue. Important issues remain outside the realm of electrophysiological techniques or are complicated by postsynaptic factors. For example, it is not known whether all presynaptic modulators affect release from all boutons in the same way, or whether modulator effects depend on the presence of certain types of voltage-gated calcium channels (VGCCs). To address such issues, we used confocal imaging and styryl dyes to monitor exocytosis from identified GABAergic boutons in organotypic hippocampal slice cultures. Repetitively evoked IPSCs declined more rapidly and completely than exocytosis, suggesting that depletion of filled vesicles cannot fully account for IPSC depression and underscoring the usefulness of directly imaging exocytosis. Stimulation at 10 Hz produced a transient facilitation of exocytosis that was dependent on L-type VGCCs. Using specific toxins, we found that release mediated via N-type and P-type VGCCs had similar properties. Neither baclofen nor a cannabinoid receptor agonist, CP55940, affected all boutons uniformly; they slowed release from some but completely prevented detectable release from others. Increasing stimulus frequency overcame this blockade of release. However, baclofen and CP55940 did not act identically, because only baclofen reduced facilitation and affected bouton releasing via P/Q-type VGCCs. Direct observation thus revealed novel features of GABAergic exocytosis and its regulation that would have been difficult or impossible to detect electrophysiologically. These features advance the understanding of the regulation of synapses and networks by presynaptic inhibition.

Key words: baclofen; cannabinoids; GABA; hippocampus; inhibition; FM1-43

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Received May 30, 2003; revised September 9, 2003; accepted September 9, 2003.

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