Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Neuroscience volume 8, pages 1319–1328 (2005)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Lisman, J.E. Relating hippocampal circuitry to function: recall of memory sequences by reciprocal dentate–CA3 interactions. Neuron 22, 233–242 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Freund, T.F. & Buzsáki, G. Interneurons of the hippocampus. Hippocampus 6, 347–470 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. McBain, C.J. & Fisahn, A. Interneurons unbound. Nat. Rev. Neurosci. 2, 11–23 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Miles, R., Tóth, K., Gulyás, A.I., Hájos, N. & Freund, T.F. Differences between somatic and dendritic inhibition in the hippocampus. Neuron 16, 815–823 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Cobb, S.R., Buhl, E.H., Halasy, K., Paulsen, O. & Somogyi, P. Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 378, 75–78 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Buzsáki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926–1929 (2004).

    Article  PubMed  Google Scholar 

  7. Mitchell, S.J. & Silver, R.A. Shunting inhibition modulates neuronal gain during synaptic excitation. Neuron 38, 433–445 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Holt, G.R. & Koch, C. Shunting inhibition does not have a divisive effect on firing rates. Neural Comput. 9, 1001–1013 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Datyner, N.B. & Gage, P.W. Phasic secretion of acetylcholine at a mammalian neuromuscular junction. J. Physiol. (Lond.) 303, 299–314 (1980).

    Article  CAS  Google Scholar 

  10. Isaacson, J.S. & Walmsley, B. Counting quanta: direct measurements of transmitter release at a central synapse. Neuron 15, 875–884 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Kraushaar, U. & Jonas, P. Efficacy and stability of quantal GABA release at a hippocampal interneuron–principal neuron synapse. J. Neurosci. 20, 5594–5607 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hefft, S., Kraushaar, U., Geiger, J.R.P. & Jonas, P. Presynaptic short-term depression is maintained during regulation of transmitter release at a GABAergic synapse in rat hippocampus. J. Physiol. (Lond.) 539, 201–208 (2002).

    Article  CAS  Google Scholar 

  13. Bartos, M. et al. Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks. Proc. Natl. Acad. Sci. USA 99, 13222–13227 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Goda, Y. & Stevens, C.F. Two components of transmitter release at a central synapse. Proc. Natl. Acad. Sci. USA 91, 12942–12946 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jensen, K., Lambert, J.D.C. & Jensen, M.S. Tetanus-induced asynchronous GABA release in cultured hippocampal neurons. Brain Res. 880, 198–201 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Otsu, Y. et al. Competition between phasic and asynchronous release for recovered synaptic vesicles at developing hippocampal autaptic synapses. J. Neurosci. 24, 420–433 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Atluri, P.P. & Regehr, W.G. Delayed release of neurotransmitter from cerebellar granule cells. J. Neurosci. 18, 8214–8227 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lu, T. & Trussell, L.O. Inhibitory transmission mediated by asynchronous transmitter release. Neuron 26, 683–694 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Rumpel, E. & Behrends, J.C. Sr2+-dependent asynchronous evoked transmission at rat striatal inhibitory synapses in vitro. J. Physiol. (Lond.) 514, 447–458 (1999).

    Article  CAS  Google Scholar 

  20. Xu-Friedman, M.A. & Regehr, W.G. Presynaptic strontium dynamics and synaptic transmission. Biophys. J. 76, 2029–2042 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Morozov, Y.M. & Freund, T.F. Postnatal development and migration of cholecystokinin-immunoreactive interneurons in rat hippocampus. Neuroscience 120, 923–939 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Freund, T.F. Interneuron diversity series: Rhythm and mood in perisomatic inhibition. Trends Neurosci. 26, 489–495 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Pawelzik, H., Hughes, D.I. & Thomson, A.M. Physiological and morphological diversity of immunocytochemically defined parvalbumin- and cholecystokinin-positive interneurones in CA1 of the adult rat hippocampus. J. Comp. Neurol. 443, 346–367 (2002).

    Article  PubMed  Google Scholar 

  24. Maccaferri, G., Roberts, J.D.B., Szucs, P., Cottingham, C.A. & Somogyi, P. Cell surface domain specific postsynaptic currents evoked by identified GABAergic neurones in rat hippocampus in vitro. J. Physiol. (Lond.) 524, 91–116 (2000).

    Article  CAS  Google Scholar 

  25. van der Kloot, W. Estimating the timing of quantal releases during end-plate currents at the frog neuromuscular junction. J. Physiol. (Lond.) 402, 595–603 (1988).

    Article  CAS  Google Scholar 

  26. Diamond, J.S. & Jahr, C.E. Asynchronous release of synaptic vesicles determines the time course of the AMPA receptor-mediated EPSC. Neuron 15, 1097–1107 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Hamann, M., Rossi, D.J. & Attwell, D. Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex. Neuron 33, 625–633 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Heinemann, S.H. & Conti, F. Nonstationary noise analysis and application to patch clamp recordings. Methods Enzymol. 207, 131–148 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Jones, M.V. & Westbrook, G.L. Desensitized states prolong GABAA channel responses to brief agonist pulses. Neuron 15, 181–191 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Brickley, S.G., Cull-Candy, S.G. & Farrant, M. Single-channel properties of synaptic and extrasynaptic GABAA receptors suggest differential targeting of receptor subtypes. J. Neurosci. 19, 2960–2973 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Poncer, J.C., McKinney, R.A., Gähwiler, B.H. & Thompson, S.M. Either N- or P-type calcium channels mediate GABA release at distinct hippocampal inhibitory synapses. Neuron 18, 463–472 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Wilson, R.I., Kunos, G. & Nicoll, R.A. Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31, 453–462 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Randall, A. & Tsien, R.W. Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons. J. Neurosci. 15, 2995–3012 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rozov, A., Burnashev, N., Sakmann, B. & Neher, E. Transmitter release modulation by intracellular Ca2+ buffers in facilitating and depressing nerve terminals of pyramidal cells in layer 2/3 of the rat neocortex indicates a target cell-specific difference in presynaptic calcium dynamics. J. Physiol. (Lond.) 531, 807–826 (2001).

    Article  CAS  Google Scholar 

  35. Neher, E. Usefulness and limitations of linear approximations to the understanding of Ca++ signals. Cell Calcium 24, 345–357 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Meinrenken, C.J., Borst, J.G.G. & Sakmann, B. Calcium secretion coupling at calyx of Held governed by nonuniform channel-vesicle topography. J. Neurosci. 22, 1648–1667 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wu, L.G., Westenbroek, R.E., Borst, J.G.G., Catterall, W.A. & Sakmann, B. Calcium channel types with distinct presynaptic localization couple differentially to transmitter release in single calyx-type synapses. J. Neurosci. 19, 726–736 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bragin, A. et al. Gamma (40–100 Hz) oscillation in the hippocampus of the behaving rat. J. Neurosci. 15, 47–60 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Matsui, K. & Jahr, C.E. Differential control of synaptic and ectopic vesicular release of glutamate. J. Neurosci. 24, 8932–8939 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Atluri, P.P. & Regehr, W.G. Determinants of the time course of facilitation at the granule cell to Purkinje cell synapse. J. Neurosci. 16, 5661–5671 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Verhage, M. et al. Differential release of amino acids, neuropeptides, and catecholamines from isolated nerve terminals. Neuron 6, 517–524 (1991).

    Article  CAS  PubMed  Google Scholar 

  42. Schmidt, H., Stiefel, K.M., Racay, P., Schwaller, B. & Eilers, J. Mutational analysis of dendritic Ca2+ kinetics in rodent Purkinje cells: role of parvalbumin and calbindin D28k . J. Physiol. (Lond.) 551, 13–32 (2003).

    Article  CAS  Google Scholar 

  43. Collin, T. et al. Developmental changes in parvalbumin regulate presynaptic Ca2+ signaling. J. Neurosci. 25, 96–107 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Südhof, T.C. Synaptotagmins: why so many? J. Biol. Chem. 277, 7629–7632 (2002).

    Article  PubMed  Google Scholar 

  45. Hui, E. et al. Three distinct kinetic groupings of the synaptotagmin family: candidate sensors for rapid and delayed exocytosis. Proc. Natl. Acad. Sci. USA 102, 5210–5214 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pouille, F. & Scanziani, M. Routing of spike series by dynamic circuits in the hippocampus. Nature 429, 717–723 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Chance, F.S., Abbott, L.F. & Reyes, A.D. Gain modulation from background synaptic input. Neuron 35, 773–782 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Losonczy, A., Biró, A.A. & Nusser, Z. Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons. Proc. Natl. Acad. Sci. USA 101, 1362–1367 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Neher, E. & Sakaba, T. Estimating transmitter release rates from postsynaptic current fluctuations. J. Neurosci. 21, 9638–9654 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang, L. & McBain, C.J. Potassium conductances underlying repolarization and afterhyperpolarization in rat CA1 hippocampal interneurones. J. Physiol. (Lond.) 488, 661–672 (1995).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Physiologisches Institut der Universität Freiburg, Hermann-Herder-Str. 7, Freiburg, D-79104, Germany

    Stefan Hefft & Peter Jonas

Authors
  1. Stefan Hefft
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Jonas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Jonas.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1542

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing