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Mol Psychiatry. 2016 Oct;21(10):1449-59. doi: 10.1038/mp.2015.203. Epub 2016 Jan 5.

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

Author information

1
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Tochigi, Japan.
3
Basic Sciences Division, Lieber Institute for Brain Development, Baltimore, MD, USA.
4
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, Kanagawa, Japan.
5
Neuroscience iMED, AstraZeneca, Cambridge, MA, USA.
6
Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
7
Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

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.

PMID:
26728564
PMCID:
PMC4935661
DOI:
10.1038/mp.2015.203
[Indexed for MEDLINE]
Free PMC Article

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