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.

Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids

Abstract

Neocortical GABA-containing interneurons form complex functional networks responsible for feedforward and feedback inhibition and for the generation of cortical oscillations associated with several behavioural functions1,2. We previously reported that fast-spiking (FS), but not low-threshold-spiking (LTS), neocortical interneurons from rats generate a fast and precise self-inhibition mediated by inhibitory autaptic transmission3. Here we show that LTS cells possess a different form of self-inhibition. LTS, but not FS, interneurons undergo a prominent hyperpolarization mediated by an increased K+-channel conductance. This self-induced inhibition lasts for many minutes, is dependent on an increase in intracellular [Ca2+] and is blocked by the cannabinoid receptor antagonist AM251, indicating that it is mediated by the autocrine release of endogenous cannabinoids. Endocannabinoid-mediated slow self-inhibition represents a powerful and long-lasting mechanism that alters the intrinsic excitability of LTS neurons, which selectively target the major site of excitatory connections onto pyramidal neurons; that is, their dendrites4,5,6,7. Thus, modulation of LTS networks after their sustained firing will lead to long-lasting changes of glutamate-mediated synaptic strength in pyramidal neurons, with consequences during normal and pathophysiological cortical network activities.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: SSI occurs in LTS, not FS, neocortical interneurons.
Figure 2: Low firing frequencies induce SSI, which reflects an increased membrane conductance.
Figure 3: Intracellular increases in [Ca2+] through voltage-dependent Ca2+ channels are required for the induction of SSI in LTS cells.
Figure 4: SSI is mediated by endocannabinoids.

References

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

    CAS  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  3. Bacci, A., Huguenard, J. R. & Prince, D. A. Functional autaptic neurotransmission in fast-spiking interneurons: a novel form of feedback inhibition in the neocortex. J. Neurosci. 23, 859–866 (2003)

    CAS  Article  PubMed  Google Scholar 

  4. Thomson, A. M. & Deuchars, J. Synaptic interactions in neocortical local circuits: dual intracellular recordings in vitro. Cereb. Cortex 7, 510–522 (1997)

    CAS  Article  PubMed  Google Scholar 

  5. Tamas, G., Buhl, E. H. & Somogyi, P. Fast IPSPs elicited via multiple synaptic release sites by different types of GABAergic neurone in the cat visual cortex. J. Physiol. (Lond.) 500, 715–738 (1997)

    CAS  Article  PubMed Central  Google Scholar 

  6. Xiang, Z., Huguenard, J. R. & Prince, D. A. Synaptic inhibition of pyramidal cells evoked by different interneuronal subtypes in layer V of rat visual cortex. J. Neurophysiol. 88, 740–750 (2002)

    Article  PubMed  Google Scholar 

  7. Williams, S. R. & Stuart, G. J. Dependence of EPSP efficacy on synapse location in neocortical pyramidal neurons. Science 295, 1907–1910 (2002)

    ADS  CAS  Article  PubMed  Google Scholar 

  8. Bacci, A., Rudolph, U., Huguenard, J. R. & Prince, D. A. Major differences in inhibitory synaptic transmission onto two neocortical interneuron subclasses. J. Neurosci. 23, 9664–9674 (2003)

    CAS  Article  PubMed  Google Scholar 

  9. Beierlein, M., Gibson, J. R. & Connors, B. W. A network of electrically coupled interneurons drives synchronized inhibition in neocortex. Nature Neurosci. 3, 904–910 (2000)

    CAS  Article  PubMed  Google Scholar 

  10. Yamada, M., Inanobe, A. & Kurachi, Y. G protein regulation of potassium ion channels. Pharmacol. Rev. 50, 723–760 (1998)

    CAS  PubMed  Google Scholar 

  11. Pouzat, C. & Marty, A. Somatic recording of GABAergic autoreceptor current in cerebellar stellate and basket cells. J. Neurosci. 19, 1675–1690 (1999)

    CAS  Article  PubMed  Google Scholar 

  12. Freund, T. F., Katona, I. & Piomelli, D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev. 83, 1017–1066 (2003)

    CAS  Article  PubMed  Google Scholar 

  13. Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691 (1994)

    ADS  CAS  Article  PubMed  Google Scholar 

  14. Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778 (1997)

    ADS  CAS  Article  PubMed  Google Scholar 

  15. Mackie, K., Lai, Y., Westenbroek, R. & Mitchell, R. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J. Neurosci. 15, 6552–6561 (1995)

    CAS  Article  PubMed  Google Scholar 

  16. Kreitzer, A. C. & Regehr, W. G. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29, 717–727 (2001)

    CAS  Article  PubMed  Google Scholar 

  17. Wilson, R. I. & Nicoll, R. A. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592 (2001)

    ADS  CAS  Article  PubMed  Google Scholar 

  18. Ohno-Shosaku, T., Maejima, T. & Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738 (2001)

    CAS  Article  PubMed  Google Scholar 

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

    ADS  CAS  Article  PubMed  Google Scholar 

  20. Trettel, J., Fortin, D. A. & Levine, E. S. Endocannabinoid signaling selectively targets perisomatic inhibitory inputs to pyramidal neurons in juvenile mouse neocortex. J. Physiol. (Lond.) 556, 95–107 (2004)

    CAS  Article  Google Scholar 

  21. Piomelli, D. The molecular logic of endocannabinoid signalling. Nature Rev. Neurosci. 4, 873–884 (2003)

    MathSciNet  CAS  Article  Google Scholar 

  22. Diana, M. A. & Marty, A. Characterization of depolarization-induced suppression of inhibition using paired interneuron–Purkinje cell recordings. J. Neurosci. 23, 5906–5918 (2003)

    CAS  Article  PubMed  Google Scholar 

  23. Kreitzer, A. C., Carter, A. G. & Regehr, W. G. Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron 34, 787–796 (2002)

    CAS  Article  PubMed  Google Scholar 

  24. Chevaleyre, V. & Castillo, P. E. Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38, 461–472 (2003)

    CAS  Article  PubMed  Google Scholar 

  25. Cravatt, B. F. et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl Acad. Sci. USA 98, 9371–9376 (2001)

    ADS  CAS  Article  PubMed  Google Scholar 

  26. Wischmeyer, E., Doring, F. & Karschin, A. Acute suppression of inwardly rectifying Kir2.1 channels by direct tyrosine kinase phosphorylation. J. Biol. Chem. 273, 34063–34068 (1998)

    CAS  Article  PubMed  Google Scholar 

  27. Galarreta, M. & Hestrin, S. A network of fast-spiking cells in the neocortex connected by electrical synapses. Nature 402, 72–75 (1999)

    ADS  CAS  Article  PubMed  Google Scholar 

  28. Gibson, J. R., Beierlein, M. & Connors, B. W. Two networks of electrically coupled inhibitory neurons in neocortex. Nature 402, 75–79 (1999)

    ADS  CAS  Article  Google Scholar 

  29. Tamas, G., Somogyi, P. & Buhl, E. H. Differentially interconnected networks of GABAergic interneurons in the visual cortex of the cat. J. Neurosci. 18, 4255–4270 (1998)

    CAS  Article  PubMed  Google Scholar 

  30. Grenier, F., Timofeev, I. & Steriade, M. Neocortical very fast oscillations (ripples, 80–200 Hz) during seizures: intracellular correlates. J. Neurophysiol. 89, 841–852 (2003)

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank I. Parada for assistance during these experiments, and J. Krey for discussions. This work was supported by grants from the National Institute of Neurological Diseases and Stroke and the Pimley Research Fund.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David A. Prince.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Table

LTS, but not FS interneurons decrease their firing frequency during SSI induction. (DOC 26 kb)

Supplementary Figure 1

LTS but not FS neocortical interneurons contain the neuropeptide CCK. (DOC 452 kb)

Supplementary Figure 2

In LTS interneurons the GIRK channel blocker Ba2+reverses both the hyperpolarization and the conductance change associated with SSI while not affecting baseline membrane potential or gm before SSI induction. (DOC 329 kb)

Supplementary Figure 3

The endocannabinoid receptor blocker AM251 applied to LTS interneurons after SSI induction reverses both membrane potential and gm, indicating a persistent CB1 receptor signaling during SSI. (DOC 352 kb)

Supplementary Figure 4

In the presence of the Na+ channel-blocker tetrodotoxin, SSI can be evoked in LTS interneurons by direct depolarization, indicating that Na+ channels are not sufficient to evoke SSI. (DOC 172 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bacci, A., Huguenard, J. & Prince, D. Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431, 312–316 (2004). https://doi.org/10.1038/nature02913

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02913

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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