Early postnatal GABA sub(A) receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1

• Published in: Molecular psychiatry 2016-10, Vol.21 (10), p.1449-1459
• Main Authors: Saito, A, Taniguchi, Y, Rannals, M D, Merfeld, E B, Ballinger, M D, Koga, M, Ohtani, Y, Gurley, D A, Sedlak, T W, Cross, A, Moss, S J, Brandon, N J, Maher, B J, Kamiya, A
• Format: Article
• Language: English
• ISSN: 1359-4184
• DOI: 10.1038/mp.2015.203

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 GABA sub(A) 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 alpha 2 subunit-containing GABA sub(A) receptors in immature developing neurons, but not after full maturation. Notably, pharmacological intervention with alpha 2/3 subtype-selective GABA sub(A) 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.