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Spatiotemporal regulation of GABA concentration in extracellular space by gliotransmission crucial for extrasynaptic receptor-mediated improvement of sensory tuning performance in schizophrenia

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Abstract

In schizophrenic patients, sensory tuning performance tends to be deteriorated (i.e., flattened sensory tuning), for which impaired intracortical tonic inhibition arising from a reduction in GABA concentration in extracellular space might be responsible. The δ subunit-containing GABAA receptor, located on extrasynaptic sites, is known to be involved in mediating tonic inhibitory currents in cortical pyramidal cells and is considered to be one of the beneficial therapeutic targets for the treatment of schizophrenia. The transporter GAT-1 in glial (astrocytic) membrane controls concentration of GABA molecules by removing them from extracellular space. We speculated that the upregulation of extrasynaptic receptors might compensate for the impaired tonic inhibition and thus improve their sensory tuning performance, in which the astrocytic GABA transporter might play an important role. To test our hypothesis, we simulated a schizophrenic neural network model with a GABAergic gliotransmission (i.e., GABA transport by transporters embedded in astrocytic membranes) mechanism that modulates local ambient (extracellular) GABA levels in a neuronal activity-dependent manner. Upregulating extrasynaptic GABA receptors compensated the impaired tonic inhibition and sharpened the sensory tuning, provided that ambient GABA molecules around stimulus-sensitive pyramidal cells were actively removed during sensory stimulation. We suggest that the upregulation of extrasynaptic GABA receptors can improve the performance of sensory tuning in schizophrenic patients, for which spatiotemporal regulation of ambient GABA concentration by gliotransmission may be crucial.

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Acknowledgments

We express our gratitude to Takeshi Kambara for his continued support and encouragement, and to the reviewers for providing their valuable insights, thoughtful suggestions and constructive comments that undoubtedly strengthened this study.

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Authors and Affiliations

  1. Department of Intelligent Systems Engineering, Ibaraki University, 4-12-1 Nakanarusawa, Hitachi, Ibaraki, 316-8511, Japan

    Osamu Hoshino

  2. Southern Tohoku Research Institute for Neuroscience, Southern Tohoku General Hospital, 7-115 Yatsuyamada, Koriyama, Fukushima, 963-8563, Japan

    Osamu Hoshino, Rikiya Kameno & Kazuo Watanabe

  3. Department of Rehabilitation Medicine, International University of Health and Welfare, Ichikawa Hospital, 6-1-14 Konodai, Ichikawa, Chiba, 272-0827, Japan

    Jin Kubo

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  1. Osamu Hoshino
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  2. Rikiya Kameno
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Correspondence to Osamu Hoshino.

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Hoshino, O., Kameno, R., Kubo, J. et al. Spatiotemporal regulation of GABA concentration in extracellular space by gliotransmission crucial for extrasynaptic receptor-mediated improvement of sensory tuning performance in schizophrenia. J Comput Neurosci 48, 317–332 (2020). https://doi.org/10.1007/s10827-020-00755-4

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