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:

Synaptic signaling between GABAergic interneurons and oligodendrocyte precursor cells in the hippocampus

Nature Neuroscience volume 7, pages 24–32 (2004)Cite this article

Abstract

Oligodendrocyte precursor cells (OPCs) express receptors for many neurotransmitters, but the mechanisms responsible for their activation are poorly understood. We have found that quantal release of GABA from interneurons elicits GABAA receptor currents with rapid rise times in hippocampal OPCs. These currents did not exhibit properties of spillover transmission or release by transporters, and immunofluorescence and electron microscopy suggest that interneuronal terminals are in direct contact with OPCs, indicating that these GABA currents are generated at direct interneuron–OPC synapses. The reversal potential of OPC GABAA currents was −43 mV, and interneuronal firing was correlated with transient depolarizations induced by GABAA receptors; however, GABA application induced a transient inhibition of currents mediated by AMPA receptors in OPCs. These results indicate that OPCs are a direct target of interneuronal collaterals and that the GABA-induced Cl− flux generated by these events may influence oligodendrocyte development by regulating the efficacy of glutamatergic signaling in OPCs.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: OPCs are inexcitable glial cells that are physiologically and morphologically distinct from astrocytes.
Figure 4: Miniature GABAA receptor–mediated currents occur in OPCs.
Figure 2: OPCs express functional GABAA receptors.
Figure 3: Increasing the firing rate of local interneurons increases the frequency of spontaneous GABAA receptor currents in OPCs.
Figure 5: GABAA receptor currents in OPCs arise from direct interneuron–OPC synapses.
Figure 6: Morphological evidence for synaptic junctions between OPCs and interneurons.
Figure 7: OPCs have high [Cl−]i and are depolarized by GABA.
Figure 8: GABA inhibits AMPA receptor currents in OPCs.

Similar content being viewed by others

References

  1. Barres, B.A., Chun, L.L. & Corey, D.P. Ion channels in vertebrate glia. Annu. Rev. Neurosci. 13, 441–474 (1990).

    Article  CAS  Google Scholar 

  2. Yuan, X., Eisen, A.M., McBain, C.J. & Gallo, V. A role for glutamate and its receptors in the regulation of oligodendrocyte development in cerebellar tissue slices. Development 125, 2901–2914 (1998).

    CAS  PubMed  Google Scholar 

  3. Stevens, B., Porta, S., Haak, L.L., Gallo, V. & Fields, R.D. Adenosine: a neuron-glia transmitter promoting myelination in the CNS in response to action potentials. Neuron 36, 855–868 (2002).

    Article  CAS  Google Scholar 

  4. Iino, M. et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001).

    Article  CAS  Google Scholar 

  5. Kang, J., Jiang, L., Goldman, S.A. & Nedergaard, M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat. Neurosci. 1, 683–692 (1998).

    Article  CAS  Google Scholar 

  6. Takano, T. et al. Glutamate release promotes growth of malignant gliomas. Nat. Med. 7, 1010–1015 (2001).

    Article  CAS  Google Scholar 

  7. Follett, P.L., Rosenberg, P.A., Volpe, J.J. & Jensen, F.E. NBQX attenuates excitotoxic injury in developing white matter. J. Neurosci. 20, 9235–9241 (2000).

    Article  CAS  Google Scholar 

  8. Barres, B.A. & Raff, M.C. Proliferation of oligodendrocyte precursor cells depends on electrical activity in axons. Nature 361, 258–260 (1993).

    Article  CAS  Google Scholar 

  9. Gallo, V. et al. Oligodendrocyte progenitor cell proliferation and lineage progression are regulated by glutamate receptor-mediated K+ channel block. J. Neurosci. 16, 2659–2670 (1996).

    Article  CAS  Google Scholar 

  10. Raff, M.C., Miller, R.H. & Noble, M. A glia progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 303, 390–396 (1983).

    Article  CAS  Google Scholar 

  11. Barres, B.A., Koroshetz, W.J., Swartz, K.J., Chun, L.L. & Corey, D.P. Ion channel expression by white matter glia: the O-2A glia progenitor cell. Neuron 4, 507–524 (1990).

    Article  CAS  Google Scholar 

  12. Patneau, D.K., Wright, P.W., Winters, C., Mayer, M.L. & Gallo, V. Glial cells of the oligodendrocyte lineage express both kainate- and AMPA-preferring subtypes of glutamate receptor. Neuron 12, 357–371 (1994).

    Article  CAS  Google Scholar 

  13. Von Blankenfeld, G., Trotter, J. & Kettenmann, H. Expression and developmental regulation of a GABAA receptor in cultured murine cells of the oligodendrocyte lineage. Eur. J. Neurosci. 3, 310–316 (1991).

    Article  Google Scholar 

  14. Williamson, A.V., Mellor, J.R., Grant, A.L. & Randall, A.D. Properties of GABAA receptors in cultured rat oligodendrocyte progenitor cells. Neuropharmacology 37, 859–873 (1998).

    Article  CAS  Google Scholar 

  15. Levison, S.W., Young, G.M. & Goldman, J.E. Cycling cells in the adult rat neocortex preferentially generate oligodendroglia. J. Neurosci. Res. 57, 435–446 (1999).

    Article  CAS  Google Scholar 

  16. Chang, A., Nishiyama, A., Peterson, J., Prineas, J. & Trapp, B.D. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J. Neurosci. 20, 6404–6412 (2000).

    Article  CAS  Google Scholar 

  17. Isaacson, J.S., Solis, J.M. & Nicoll, R.A. Local and diffuse synaptic actions of GABA in the hippocampus. Neuron 10, 165–175 (1993).

    Article  CAS  Google Scholar 

  18. Clark, B.A. & Cull-Candy, S.G. Activity-dependent recruitment of extrasynaptic NMDA receptor activation at an AMPA receptor-only synapse. J. Neurosci. 22, 4428–4436 (2002).

    Article  CAS  Google Scholar 

  19. Bergles, D.E., Dzubay, J.A. & Jahr, C.E. Glutamate transporter currents in bergmann glial cells follow the time course of extrasynaptic glutamate. Proc. Natl. Acad. Sci. USA 94, 14821–14825 (1997).

    Article  CAS  Google Scholar 

  20. Porter, J.T. & McCarthy, K.D. Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J. Neurosci. 16, 5073–5081 (1996).

    Article  CAS  Google Scholar 

  21. Dzubay, J.A. & Jahr, C.E. The concentration of synaptically released glutamate outside of the climbing fiber-Purkinje cell synaptic cleft. J. Neurosci. 19, 5265–5274 (1999).

    Article  CAS  Google Scholar 

  22. Bergles, D.E., Roberts, J.D., Somogyi, P. & Jahr, C.E. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405, 187–191 (2000).

    Article  CAS  Google Scholar 

  23. Steinhauser, C., Berger, T., Frotscher, M. & Kettenmann, H. Heterogeneity in the membrane current pattern of identified glial cells in the hippocampal slice. Eur. J. Neurosci. 4, 472–484 (1992).

    Article  Google Scholar 

  24. Levine, J.M., Reynolds, R. & Fawcett, J.W. The oligodendrocyte precursor cell in health and disease. Trends Neurosci. 24, 39–47 (2001).

    Article  CAS  Google Scholar 

  25. Pitler, T.A. & Alger, B.E. Cholinergic excitation of GABAergic interneurons in the rat hippocampal slice. J. Physiol. 450, 127–142 (1992).

    Article  CAS  Google Scholar 

  26. Sciancalepore, M., Savic, N., Gyori, J. & Cherubini, E. Facilitation of miniature GABAergic currents by ruthenium red in neonatal rat hippocampal neurons. J. Neurophysiol. 80, 2316–2322 (1998).

    Article  CAS  Google Scholar 

  27. Overstreet, L.S., Jones, M.V. & Westbrook, G.L. Slow desensitization regulates the availability of synaptic GABAA receptors. J. Neurosci. 20, 7914–7921 (2000).

    Article  CAS  Google Scholar 

  28. Perrais, D. & Ropert, N. Effect of zolpidem on miniature IPSCs and occupancy of postsynaptic GABAA receptors in central synapses. J. Neurosci. 19, 578–588 (1999).

    Article  CAS  Google Scholar 

  29. Hajos, N., Nusser, Z., Rancz, E.A., Freund, T.F. & Mody, I. Cell type- and synapse-specific variability in synaptic GABAA receptor occupancy. Eur. J. Neurosci. 12, 810–818 (2000).

    Article  CAS  Google Scholar 

  30. Lavoie, A.M. & Twyman, R.E. Direct evidence for diazepam modulation of GABAA receptor microscopic affinity. Neuropharmacology 35, 1383–1392 (1996).

    Article  CAS  Google Scholar 

  31. Frerking, M., Borges, S. & Wilson, M. Variation in GABA mini amplitude is the consequence of variation in transmitter concentration. Neuron 15, 885–895 (1995).

    Article  CAS  Google Scholar 

  32. Owens, D.F., Boyce, L.H., Davis, M.B. & Kriegstein, A.R. Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated-patch recordings and calcium imaging. J. Neurosci. 16, 6414–6423 (1996).

    Article  CAS  Google Scholar 

  33. Gilbert, P., Kettenmann, H. & Schachner, M. Gamma-aminobutyric acid directly depolarizes cultured oligodendrocytes. J. Neurosci. 4, 561–569 (1984).

    Article  CAS  Google Scholar 

  34. Ebihara, S., Shirato, K., Harata, N. & Akaike, N. Gramicidin-perforated patch recording: GABA response in mammalian neurones with intact intracellular chloride. J. Physiol. 484, 77–86 (1995).

    Article  CAS  Google Scholar 

  35. Van Damme, P., Callewaert, G., Eggermont, J., Robberecht, W. & Van Den Bosch, L. Chloride influx aggravates Ca2+-dependent AMPA receptor-mediated motoneuron death. J. Neurosci. 23, 4942–4950 (2003).

    Article  CAS  Google Scholar 

  36. Mody, I. Distinguishing between GABAA receptors responsible for tonic and phasic conductances. Neurochem. Res. 26, 907–913 (2001).

    Article  CAS  Google Scholar 

  37. Cohen, A.S., Lin, D.D. & Coulter, D.A. Protracted postnatal development of inhibitory synaptic transmission in rat hippocampal area CA1 neurons. J. Neurophysiol. 84, 2465–2476 (2000).

    Article  CAS  Google Scholar 

  38. Goldstein, P.A. et al. Prolongation of hippocampal miniature inhibitory postsynaptic currents in mice lacking the GABAA receptor alpha1 subunit. J. Neurophysiol. 88, 3208–3217 (2002).

    Article  CAS  Google Scholar 

  39. Burgard, E.C., Tietz, E.I., Neelands, T.R. & Macdonald, R.L. Properties of recombinant gamma-aminobutyric acid A receptor isoforms containing the alpha 5 subunit subtype. Mol. Pharmacol. 50, 119–127 (1996).

    CAS  PubMed  Google Scholar 

  40. Brunig, I., Scotti, E., Sidler, C. & Fritschy, J.M. Intact sorting, targeting, and clustering of gamma-aminobutyric acid A receptor subtypes in hippocampal neurons in vitro. J. Comp. Neurol. 443, 43–55 (2002).

    Article  CAS  Google Scholar 

  41. Collinson, N. et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J. Neurosci. 22, 5572–5580 (2002).

    Article  CAS  Google Scholar 

  42. Pastor, A., Chvatal, A., Sykova, E. & Kettenmann, H. Glycine- and GABA-activated currents in identified glial cells of the developing rat spinal cord slice. Eur. J. Neurosci. 7, 1188–1198 (1995).

    Article  CAS  Google Scholar 

  43. Mudrick-Donnon, L.A., Williams, P.J., Pittman, Q.J. & MacVicar, B.A. Postsynaptic potentials mediated by GABA and dopamine evoked in stellate glial cells of the pituitary pars intermedia. J. Neurosci. 13, 4660–4668 (1993).

    Article  CAS  Google Scholar 

  44. Theodosis, D.T. & MacVicar, B. Neurone-glia interactions in the hypothalamus and pituitary. Trends Neurosci. 19, 363–367 (1996).

    Article  CAS  Google Scholar 

  45. Ganguly, K., Schinder, A.F., Wong, S.T. & Poo, M. GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition. Cell 105, 521–532 (2001).

    Article  CAS  Google Scholar 

  46. Staley, K.J., Soldo, B.L. & Proctor, W.R. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 269, 977–981 (1995).

    Article  CAS  Google Scholar 

  47. Tillet, E., Ruggiero, F., Nishiyama, A. & Stallcup, W.B. The membrane-spanning proteoglycan NG2 binds to collagens V and VI through the central nonglobular domain of its core protein. J. Biol. Chem. 272, 10769–10776 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Jahr for support during the initial part of this work, P. Somogyi and J.D.B. Roberts for their help with electron microscopy and S.H. Kong for help with cryosectioning. Supported by the Sloan Foundation and a Basil O'Connor Scholar Award from the March of Dimes Foundation.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, WBSB 813, Baltimore, 21205, Maryland, USA

    Shih-chun Lin & Dwight E Bergles

Authors
  1. Shih-chun Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dwight E Bergles
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dwight E Bergles.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Stimulus evoked release of glutamate and GABA onto OPCs. (a) A single stimulation to Schaffer collateral-commissural fibers with a bipolar electrode elicited an inward current in an OPC that had a rapid onset (black trace). Bath application of 5 µM NBQX decreased the amplitude of this response (red trace), indicating that AMPA receptors contributed to this current. The decrease in amplitude is also likely to have resulted from a decrease in polysynaptic excitation. (b) Subsequent application of SR-95531 (5 µM) blocked the remaining current (red trace), indicating that it was mediated by GABAA receptors. Note the rapid onset of the inward current following stimulation. CsCl-based internal solution. Vm = -70 mV. (GIF 4 kb)

Supplementary Fig. 2

Effects of carbachol and SKF 89976-A on OPCs. (a) Bath application of SKF 89976-A (100 µM) did not induce a change in holding current in an OPC located in the stratum radiatum region of the hippocampus. The recording was made with a CsCl-based internal solution and the ACSF contained 5 µM NBQX and 5 µM RS-CPP. Holding potential = -70 mV. Similar results were observed in 4/4 cells. (b) Bath application of carbachol (5 µM) did not alter the holding current of an OPC. The recoding was made with a CsMeS-based internal solution and the ACSF contained 5 µM NBQX, 5 µM RS-CPP and 1 µM TTX. Vm = +40 mV. Similar results were observed in 5/5 cells. (c) Carbachol (5 µM) did not change the membrane potential of an OPC. Gramicidin perforated-patch recording, KCl internal solution. Similar results were obtained in 4/4 cells. (GIF 10 kb)

Supplementary Fig. 3

Test of GABA release by OPCs. Whole-cell voltage-clamp recording from an OPC with a CsCl-based internal solution containing 10 mM GABA and 0.1 mM EGTA. A 50 ms step from -70 mV to +5 mV (lower trace) produced an outward current (upper traces) but did not induce an inward current upon repolarization, as would be expected if the depolarization induced release of GABA and auto activation of GABAA receptors on this cell. Responses recorded with and without SR-95531 (5 µM) are overlaid. The ACSF contained 5 µM NBQX and 5 µM RS-CPP. Similar results were obtained in 6/6 recordings from OPCs. (GIF 4 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, Sc., Bergles, D. Synaptic signaling between GABAergic interneurons and oligodendrocyte precursor cells in the hippocampus. Nat Neurosci 7, 24–32 (2004). https://doi.org/10.1038/nn1162

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1162

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