Differential dependence of phasic transmitter release on synaptotagmin 1 at GABAergic and glutamatergic hippocampal synapses

Abstract

Previous studies revealed that synaptotagmin 1 is the major Ca 2؉ sensor for fast synchronous transmitter release at excitatory synapses. However, the molecular identity of the Ca 2؉ sensor at hippocampal inhibitory synapses has not been determined. To address the functional role of synaptotagmin 1 at identified inhibitory terminals, we made paired recordings from synaptically connected basket cells (BCs) and granule cells (GCs) in the dentate gyrus in organotypic slice cultures from wild-type and synaptotagmin 1-deficient mice. As expected, genetic elimination of synaptotagmin 1 abolished synchronous transmitter release at excitatory GC-BC synapses. However, synchronous release at inhibitory BC-GC synapses was maintained. Quantitative analysis revealed that elimination of synaptotagmin 1 reduced release probability and depression but maintained the synchrony of transmitter release at BC-GC synapses. Elimination of synaptotagmin 1 also increased the frequency of both miniature excitatory postsynaptic currents (measured in BCs) and miniature inhibitory postsynaptic currents (recorded in GCs), consistent with a clamping function of synaptotagmin 1 at both excitatory and inhibitory terminals. Single-cell reverse-transcription quantitative PCR analysis revealed that single BCs coexpressed multiple synaptotagmin isoforms, including synaptotagmin 1-5, 7, and 11-13. Our results indicate that, in contrast to excitatory synapses, synaptotagmin 1 is not absolutely required for synchronous release at inhibitory BC-GC synapses. Thus, alternative fast Ca 2؉ sensors contribute to synchronous release of the inhibitory transmitter GABA in cortical circuits.GABAergic interneurons ͉ basket cells ͉ hippocampus ͉ Ca 2ϩ sensor G ABAergic interneurons of the basket cell subtype (BCs) play a key role in neuronal network function. These interneurons control the average activity level in principal neurons via fast feed-forward and feedback inhibition (1) and are involved in the generation of network oscillations in the ␥-frequency range (2). BCs receive a fast excitatory synaptic input, which allows them to detect coincident activity of principal neurons (3). Furthermore, BCs generate rapid inhibitory output signals in their target cells (4). Previous studies revealed that transmitter release at BC output synapses is exclusively mediated by P/Q-type Ca 2ϩ channels (5, 6) and that these Ca 2ϩ channels are tightly coupled to the Ca 2ϩ sensors of exocytosis, with coupling distances of 10-20 nm (7). Tight coupling contributes to fast signaling, increasing the speed and temporal precision of transmitter release.Expression of specialized Ca 2ϩ sensors of exocytosis may also contribute to the speed and temporal precision of synaptic transmission. However, the synaptic Ca 2ϩ sensors that mediate glutamatergic BC input and GABAergic BC output have not yet been identified. At several synapses, synaptotagmin 1 is essential for fast transmitter release (8-11). Genetic elimination of synaptotagmin 1 abolishes synchronous release in both glutamatergi...

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