Abstract
Activity-dependent synapse refinement is crucial for the formation of precise excitatory and inhibitory neuronal circuits. Whereas the mechanisms that guide refinement of excitatory circuits are becoming increasingly clear, the mechanisms guiding inhibitory circuits have remained obscure. In the lateral superior olive (LSO), a nucleus in the mammalian sound localization system that receives inhibitory input from the medial nucleus of the trapezoid body (MNTB), specific elimination and strengthening of synapses that are both GABAergic and glycinergic (GABA/glycinergic synapses) is essential for the formation of a precise tonotopic map. We provide evidence that immature GABA/glycinergic synapses in the rat LSO also release the excitatory neurotransmitter glutamate, which activates postsynaptic NMDA receptors (NMDARs). Immunohistochemical studies demonstrate synaptic colocalization of the vesicular glutamate transporter 3 with the vesicular GABA transporter, indicating that GABA, glycine and glutamate are released from single MNTB terminals. Glutamatergic transmission at MNTB-LSO synapses is most prominent during the period of synapse elimination. Synapse-specific activation of NMDARs by glutamate release at GABAergic and glycinergic synapses could be important in activity-dependent refinement of inhibitory circuits.
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References
Katz, L.C. & Shatz, C.J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996).
Hendry, S.H. & Jones, E.G. Reduction in number of immunostained GABAergic neurones in deprived-eye dominance columns of monkey area 17. Nature 320, 750–753 (1986).
Otis, T.S., DeKoninck, Y. & Mody, I. Lasting potentiation of inhibition is associated with an increased number of gamma-aminobutyric acid type A receptors activated during miniature inhibitory postsynaptic currents. Proc. Natl. Acad. Sci. USA 91, 7698–7702 (1994).
Micheva, K.D. & Beaulieu, C. An anatomical substrate for experience-dependent plasticity of the rat barrel field cortex. Proc. Natl. Acad. Sci. USA 92, 11834–11838 (1995).
Korada, S. & Schwartz, I.R. Development of GABA, glycine, and their receptors in the auditory brainstem of gerbil: a light and electron microscopic study. J. Comp. Neurol. 409, 664–681 (1999).
Kilman, V., van Rossum, M.C. & Turrigiano, G.G. Activity deprivation reduces miniature IPSC amplitude by decreasing the number of postsynaptic GABA(A) receptors clustered at neurocortical synapses. J. Neurosci. 22, 1328–1337 (2002).
Woodin, M.A., Ganguly, K. & Poo, M.M. Coincident pre- and postsynaptic activity modifies GABAergic synapses by postsynaptic changes in Cl− transporter activity. Neuron 39, 807–820 (2003).
Kandler, K. Activity-dependent organization of inhibitory circuits: lessons from the auditory system. Curr. Opin. Neurobiol. 14, 96–104 (2004).
Boudreau, J.C. & Tsuchitani, C. Binaural interaction in the cat superior olive S segment. J. Neurophysiol. 31, 442–454 (1968).
Moore, M.J. & Caspary, D.M. Strychnine blocks binaural inhibition in lateral superior olivary neurons. J. Neurosci. 3, 237–242 (1983).
Kotak, V.C., Korada, S., Schwartz, I.R. & Sanes, D.H. A developmental shift from GABAergic to glycinergic transmission in the central auditory system. J. Neurosci. 18, 4646–4655 (1998).
Nabekura, J. et al. Developmental switch from GABA to glycine release in single central synaptic terminals. Nat. Neurosci. 7, 17–23 (2004).
Kim, G. & Kandler, K. Elimination and strengthening of glycinergic/GABAergic connections during tonotopic map formation. Nat. Neurosci. 6, 282–290 (2003).
Sanes, D.H. & Friauf, E. Development and influence of inhibition in the lateral superior olivary nucleus. Hear. Res. 147, 46–58 (2000).
Kandler, K. & Friauf, E. Development of glycinergic and glutamatergic synaptic transmission in the auditory brainstem of perinatal rats. J. Neurosci. 15, 6890–6904 (1995).
Ahmadi, S. et al. Facilitation of spinal NMDA receptor currents by spillover of synaptically released glycine. Science 300, 2094–2097 (2003).
Schwartz, I. The superior olivary complex and lateral lemniscal nuclei. in The Mammalian Auditory Pathway: Neuroanatomy (eds. Popper, A.N., Fay, R.R. & Webster, D.B.) 117–167 (Springer, New York, 1992).
Chatterton, J.E. et al. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415, 793–798 (2002).
Kullmann, P.H. & Kandler, K. Glycinergic/GABAergic synapses in the lateral superior olive are excitatory in neonatal C57B1/6J mice. Brain Res. Dev. Brain Res. 131, 143–147 (2001).
Lohmann, C., Ehrlich, I. & Friauf, E. Axon regeneration in organotypic slice cultures from the mammalian auditory system is topographic and functional. J. Neurobiol. 41, 596–611 (1999).
Stevens, C.F. & Wang, Y. Facilitation and depression at single central synapses. Neuron 14, 795–802 (1995).
Aamodt, S.M., Shi, J., Colonnese, M.T., Veras, W. & Constantine-Paton, M. Chronic NMDA exposure accelerates development of GABAergic inhibition in the superior colliculus. J. Neurophysiol. 83, 1580–1591 (2000).
Gaiarsa, J.L., Caillard, O. & Ben-Ari, Y. Long-term plasticity at GABAergic and glycinergic synapses: mechanisms and functional significance. Trends Neurosci. 25, 564–570 (2002).
Dickson, K.S. & Kind, P.C. NMDA receptors: neural map designers and refiners? Curr. Biol. 13, R920–R922 (2003).
Ehrlich, I., Lohrke, S. & Friauf, E. Shift from depolarizing to hyperpolarizing glycine action in rat auditory neurons is due to age-dependent Cl− regulation. J. Physiol. (Lond.) 520, 121–137 (1999).
Fon, E.A. & Edwards, R.H. Molecular mechanisms of neurotransmitter release. Muscle Nerve 24, 581–601 (2001).
Helfert, R.H., Bonneau, J.M., Wenthold, R.J. & Altschuler, R.A. GABA and glycine immunoreactivity in the guinea pig superior olivary complex. Brain Res. 501, 269–286 (1989).
Bledsoe, S.C. Jr. et al. Immunocytochemical and lesion studies support the hypothesis that the projection from the medial nucleus of the trapezoid body to the lateral superior olive is glycinergic. Brain Res. 517, 189–194 (1990).
Docherty, M., Bradford, H.F. & Wu, J.Y. Co-release of glutamate and aspartate from cholinergic and GABAergic synaptosomes. Nature 330, 64–66 (1987).
O'Malley, D.M. & Masland, R.H. Co-release of acetylcholine and gamma-a2inobutyric acid by a retinal neuron. Proc. Natl. Acad. Sci. USA 86, 3414–3418 (1989).
Jonas, P., Bischofberger, J. & Sandkuhler, J. Corelease of two fast neurotransmitters at a central synapse. Science 281, 419–424 (1998).
Walker, M.C., Ruiz, A. & Kullmann, D.M. Monosynaptic GABAergic signaling from dentate to CA3 with a pharmacological and physiological profile typical of mossy fiber synapses. Neuron 29, 703–715 (2001).
Gutierrez, R. et al. Plasticity of the GABAergic phenotype of the 'glutamatergic' granule cells of the rat dentate gyrus. J. Neurosci. 23, 5594–5598 (2003).
Glendenning, K.K., Masterton, R.B., Baker, B.N. & Wenthold, R.J. Acoustic chiasm. III: Nature, distribution, and sources of afferents to the lateral superior olive in the cat. J. Comp. Neurol. 310, 377–400 (1991).
Helfert, R.H. et al. Patterns of glutamate, glycine, and GABA immunolabeling in four synaptic terminal classes in the lateral superior olive of the guinea pig. J. Comp. Neurol. 323, 305–325 (1992).
Kullmann, P.H., Ene, F.A. & Kandler, K. Glycinergic and GABAergic calcium responses in the developing lateral superior olive. Eur. J. Neurosci. 15, 1093–1104 (2002).
Ene, F.A., Kullmann, P.H., Gillespie, D.C. & Kandler, K. Glutamatergic calcium responses in the developing lateral superior olive: receptor types and their specific activation by synaptic activity patterns. J. Neurophysiol. 90, 2581–2591 (2003).
Ben-Ari, Y., Khazipov, R., Leinekugel, X., Caillard, O. & Gaiarsa, J.L. GABAA, NMDA and AMPA receptors: a developmentally regulated 'menage a trois'. Trends Neurosci. 20, 523–529 (1997).
Bellocchio, E.E., Reimer, R.J., Fremeau, R.T. & Edwards, R.H. Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science 289, 957–960 (2000).
Wojcik, S.M. et al. An essential role for vesicular glutamate transporter 1 (VGLUT1) in postnatal development and control of quantal size. Proc. Natl. Acad. Sci. USA 101, 7158–7163 (2004).
Fremeau, R.T. et al. Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science 304, 1815–1819 (2004).
Fremeau, R.T. Jr., Voglmaier, S., Seal, R.P. & Edwards, R.H. VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci. 27, 98–103 (2004).
Harkany, T. et al. Endocannabinoid-independent retrograde signaling at inhibitory synapses in layer 2/3 of neocortex: involvement of vesicular glutamate transporter 3. J. Neurosci. 24, 4978–4988 (2004).
Lynch, J.W. Molecular structure and function of the glycine receptor chloride channel. Physiol. Rev. 84, 1051–1095 (2004).
Malinow, R. AMPA receptor trafficking and long-term potentiation. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358, 707–714 (2003).
Furuta, A., Rothstein, J.D. & Martin, L.J. Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J. Neurosci. 17, 8363–8375 (1997).
McLean, H.A., Caillard, O., Ben-Ari, Y. & Gaiarsa, J.L. Bidirectional plasticity expressed by GABAergic synapses in the neonatal rat hippocampus. J. Physiol. (Lond.) 496, 471–477 (1996).
Morishita, W. & Sastry, B.R. Postsynaptic mechanisms underlying long-term depression of GABAergic transmission in neurons of the deep cerebellar nuclei. J. Neurophysiol. 76, 59–68 (1996).
Givens, R.S., Weber, J.F., Jung, A.H. & Park, C.H. New photoprotecting groups: desyl and p-hydroxyphenacyl phosphate and carboxylate esters. Methods Enzymol. 291, 1–29 (1998).
Acknowledgements
The authors thank K. Cihil for technical assistance, R. Edwards for VGAT and VGLUT1/2 antibodies, R. Givens for caged glutamate, W. Halfter for SV2 antibodies, and P. Land, S. Shand and S. Watkins for lending histology advice and equipment. We are grateful to E. Aizenman, S. Amara, N.K. Baba, J. Johnson and L. Lillien for comments on an earlier version of the manuscript. This work was supported by grants from the National Institute on Deafness and Other Communication Disorders (K.K., D.C.G.) and the National Institute of Neurological Disorders and Stroke (D.C.G.).
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Gillespie, D., Kim, G. & Kandler, K. Inhibitory synapses in the developing auditory system are glutamatergic. Nat Neurosci 8, 332–338 (2005). https://doi.org/10.1038/nn1397
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DOI: https://doi.org/10.1038/nn1397
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