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Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1

Molecular Psychiatry volume 21, pages 1449–1459 (2016)Cite this article

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Abstract

Exploring drug targets based on disease-associated molecular mechanisms during development is crucial for the generation of novel prevention and treatment strategies for neurodevelopmental psychiatric conditions. We report that prefrontal cortex (PFC)-specific postnatal knockdown of DISC1 via in utero electroporation combined with an inducible knockdown expression system drives deficits in synaptic GABAA function and dendritic development in pyramidal neurons, as well as abnormalities in sensorimotor gating, albeit without profound memory deficits. We show for the first time that DISC1 is specifically involved in regulating cell surface expression of α2 subunit-containing GABAA receptors in immature developing neurons, but not after full maturation. Notably, pharmacological intervention with α2/3 subtype-selective GABAA receptor positive allosteric modulators during the early postnatal period ameliorates dendritic deficits and behavioral abnormalities induced by knockdown of DISC1. These findings highlight a critical role of DISC1-mediated disruption of postnatal GABA signaling in aberrant PFC maturation and function.

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Acknowledgements

We thank Pamela Talalay and Keri Martinowich, as well as Ms Nada Rendradjaja for critical reading of the manuscript. We thank Kozo Kaibuchi and Keisuke Kuroda for providing us with DISC1 antibodies and Dr Miho Terunuma for advice on biotinylation assays. This work was supported by R01 MH-091230 (AK), P50 MH-094268 (AK), R21AT008547 (AK), K01 MH-086050 (BJM), Brain & Behavior Research Foundation (AK) and Brain Science Foundation (AK).

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Author notes

  1. A Saito and Y Taniguchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    A Saito, Y Taniguchi, E B Merfeld, M D Ballinger, M Koga, Y Ohtani, T W Sedlak, B J Maher & A Kamiya

  2. Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Tochigi, Japan

    A Saito

  3. Basic Sciences Division, Lieber Institute for Brain Development, Baltimore, MD, USA

    M D Rannals & B J Maher

  4. Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, Kanagawa, Japan

    Y Ohtani

  5. Neuroscience iMED, AstraZeneca, Cambridge, MA, USA

    D A Gurley, A Cross & N J Brandon

  6. Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA

    S J Moss

  7. Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK

    S J Moss

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  1. A Saito
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Correspondence to A Kamiya.

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Competing interests

AC and NJB are full-time employees and shareholders in AstraZeneca. SJM serves as a consultant for SAGE therapeutics and AstraZeneca, relationships that are regulated by Tufts University.

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Saito, A., Taniguchi, Y., Rannals, M. et al. Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1. Mol Psychiatry 21, 1449–1459 (2016). https://doi.org/10.1038/mp.2015.203

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