Asynchronous GABA release generates long-lasting inhibition at a hippocampal interneuron–principal neuron synapse

Abstract

Hippocampal GABAergic interneurons show diverse molecular and morphological properties. The functional significance of this diversity for information processing is poorly understood. Here we show that cholecystokinin (CCK)-expressing interneurons in rat dentate gyrus release GABA in a highly asynchronous manner, in contrast to parvalbumin (PV) interneurons. With a gamma-frequency burst of ten action potentials, the ratio of asynchronous to synchronous release is 3:1 in CCK interneurons but is 1:5 in parvalbumin interneurons. N-type channels trigger synchronous and asynchronous release in CCK interneuron synapses, whereas P/Q-type Ca2+ channels mediate release at PV interneuron synapses. Effects of Ca2+ chelators suggest that both a long-lasting presynaptic Ca2+ transient and a large distance between Ca2+ source and sensor of exocytosis contribute to the higher ratio of asynchronous to synchronous release in CCK interneuron synapses. Asynchronous release occurs at physiological temperature and with behaviorally relevant stimulation patterns, thus generating long-lasting inhibition in the brain.

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Figure 1: CCK- and PV-positive interneurons in the dentate gyrus have adjacent, but largely non-overlapping, axonal arborizations.
Figure 2: Output synapses of CCK interneurons and PV interneurons differ in basic properties of GABA release.
Figure 3: Asynchronous release at CCK interneuron output synapses.
Figure 4: Ratio of asynchronous to synchronous release in CCK and PV interneuron–granule cell synapses.
Figure 5: Different Ca2+ channels mediate transmission in CCK and PV interneuron synapses.
Figure 6: Differential effects of Ca2+ chelators on transmitter release in CCK and PV interneuron synaptic terminals.
Figure 7: Dependence of asynchronous release from CCK terminals on number and frequency of presynaptic action potentials.
Figure 8: Asynchronous release from CCK interneuron synapses at near-physiological temperature and with theta-burst stimulation patterns.

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Acknowledgements

We thank J. Bischofberger for support at the confocal microscope and for many discussions; I. Vida and A. Kulik for help with immunocytochemistry; M. Bartos, J. Behrends, J. Bischofberger, K. Haverkampf and M. Heckmann for reading the manuscript and K. Winterhalter and M. Northemann for excellent technical assistance. Supported by the Deutsche Forschungsgemeinschaft (SFB 505, project C5).

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Correspondence to Peter Jonas.

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Hefft, S., Jonas, P. Asynchronous GABA release generates long-lasting inhibition at a hippocampal interneuron–principal neuron synapse. Nat Neurosci 8, 1319–1328 (2005). https://doi.org/10.1038/nn1542

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