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.
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References
Barres, B.A., Chun, L.L. & Corey, D.P. Ion channels in vertebrate glia. Annu. Rev. Neurosci. 13, 441–474 (1990).
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).
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).
Iino, M. et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001).
Kang, J., Jiang, L., Goldman, S.A. & Nedergaard, M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat. Neurosci. 1, 683–692 (1998).
Takano, T. et al. Glutamate release promotes growth of malignant gliomas. Nat. Med. 7, 1010–1015 (2001).
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).
Barres, B.A. & Raff, M.C. Proliferation of oligodendrocyte precursor cells depends on electrical activity in axons. Nature 361, 258–260 (1993).
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).
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).
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).
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).
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).
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).
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).
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).
Isaacson, J.S., Solis, J.M. & Nicoll, R.A. Local and diffuse synaptic actions of GABA in the hippocampus. Neuron 10, 165–175 (1993).
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).
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).
Porter, J.T. & McCarthy, K.D. Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J. Neurosci. 16, 5073–5081 (1996).
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).
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).
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).
Levine, J.M., Reynolds, R. & Fawcett, J.W. The oligodendrocyte precursor cell in health and disease. Trends Neurosci. 24, 39–47 (2001).
Pitler, T.A. & Alger, B.E. Cholinergic excitation of GABAergic interneurons in the rat hippocampal slice. J. Physiol. 450, 127–142 (1992).
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).
Overstreet, L.S., Jones, M.V. & Westbrook, G.L. Slow desensitization regulates the availability of synaptic GABAA receptors. J. Neurosci. 20, 7914–7921 (2000).
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).
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).
Lavoie, A.M. & Twyman, R.E. Direct evidence for diazepam modulation of GABAA receptor microscopic affinity. Neuropharmacology 35, 1383–1392 (1996).
Frerking, M., Borges, S. & Wilson, M. Variation in GABA mini amplitude is the consequence of variation in transmitter concentration. Neuron 15, 885–895 (1995).
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).
Gilbert, P., Kettenmann, H. & Schachner, M. Gamma-aminobutyric acid directly depolarizes cultured oligodendrocytes. J. Neurosci. 4, 561–569 (1984).
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).
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).
Mody, I. Distinguishing between GABAA receptors responsible for tonic and phasic conductances. Neurochem. Res. 26, 907–913 (2001).
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).
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).
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).
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).
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).
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).
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).
Theodosis, D.T. & MacVicar, B. Neurone-glia interactions in the hypothalamus and pituitary. Trends Neurosci. 19, 363–367 (1996).
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).
Staley, K.J., Soldo, B.L. & Proctor, W.R. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 269, 977–981 (1995).
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).
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.
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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)
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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
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DOI: https://doi.org/10.1038/nn1162
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