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Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map

Nature Neuroscience volume 13, pages 232–238 (2010)Cite this article

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Abstract

Many nonglutamatergic synaptic terminals in the mammalian brain contain the vesicular glutamate transporter 3 (VGLUT3), indicating that they co-release the excitatory neurotransmitter glutamate. However, the functional role of glutamate co-transmission at these synapses is poorly understood. In the auditory system, VGLUT3 expression and glutamate co-transmission are prominent in a developing GABA/glycinergic sound-localization pathway. We found that mice with a genetic deletion of Vglut3 (also known as Slc17a8) had disrupted glutamate co-transmission and severe impairment in the refinement of this inhibitory pathway. Specifically, loss of glutamate co-transmission disrupted synaptic silencing and the strengthening of GABA/glycinergic connections that normally occur with maturation. Functional mapping studies further revealed that these deficits markedly degraded the precision of tonotopy in this inhibitory auditory pathway. These results indicate that glutamate co-transmission is crucial for the synaptic reorganization and topographic specification of a developing inhibitory circuit.

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Figure 1: VGLUT3 expression is required for glutamate co-transmission at GABA/glycinergic MNTB-LSO synapses.
Figure 2: Strengthening of single-fiber MNTB-LSO connections is impaired in Vglut3−/− mice.
Figure 3: Paired-pulse responses in LSO neurons from Vglut3+/+ and Vglut3−/− mice (P9–12).
Figure 4: Disruption of glutamate co-transmission impairs the developmental strengthening of all converging MNTB inputs.
Figure 5: Topographic sharpening of MNTB-LSO input maps is impaired in Vglut3−/− mice.
Figure 6: Membrane properties of MNTB neurons and spatial resolution of glutamate photolysis in the MNTB are not different in Vglut3+/+ and Vglut3−/− mice.
Figure 7: Glutamatergic cochlear nucleus–LSO inputs are normal in Vglut3−/− mice.
Figure 8: Normal glutamate co-transmission at MNTB-LSO synapses in Otoferlin knockout mice (Otof−/−).

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Acknowledgements

We thank D. Gillespie for initial recordings from Vglut3−/– mice and K. Cihil for help with genotyping. Otoferlin knockout mice (pachanga)37 were generously supplied by U. Mueller (Scripps Institute). We are grateful to E. Aizenman, J. Castro, A. Clause and T. Tzounopoulos for comments on the manuscript. K.K. was supported by the National Institute on Deafness and Other Communication Disorders (DC-04199), R.P.S. by the National Alliance for Research on Schizophrenia and Depression and R.H.E. by the National Institute on Drug Abuse and the National Institute of Mental Health.

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  1. Jihyun Noh

    Present address: Present address: Department of Life Sciences and Division of Life & Pharmaceutical Sciences, Ewha Womans University, Daehyun-dong, Seodaemun-Gu, Seoul, Korea.,

Authors and Affiliations

  1. Department of Otolaryngology, University of Pittsburgh School of Medicine, Eye and Ear Institute, Pittsburgh, Pennsylvania, USA

    Jihyun Noh, Jessica A Garver & Karl Kandler

  2. Department of Neurobiology, University of Pittsburgh School of Medicine, Eye and Ear Institute, Pittsburgh, Pennsylvania, USA

    Jihyun Noh & Karl Kandler

  3. Departments of Neurology and Physiology, School of Medicine, University of California at San Francisco, San Francisco, California, USA

    Rebecca P Seal & Robert H Edwards

  4. Center for the Neural Basis of Cognition, University of Pittsburgh and Carnegie Mellon, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Karl Kandler

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Contributions

J.N. conducted electrophysiological experiments and data analysis, R.P.S. and R.H.E. created the Vglut3−/− mice and participated in the study design, J.A.G. conducted genotyping and participated in data analysis, J.N. and K.K. designed the experiments and J.N., R.P.S., R.H.E. and K.K. wrote the paper.

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Correspondence to Karl Kandler.

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Noh, J., Seal, R., Garver, J. et al. Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map. Nat Neurosci 13, 232–238 (2010). https://doi.org/10.1038/nn.2478

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