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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Electroporation
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / physiology
  • Neurogenesis / drug effects
  • Neurons / drug effects
  • Prefrontal Cortex / metabolism
  • Protein Subunits
  • Pyramidal Cells / metabolism
  • Receptors, GABA-A / drug effects*
  • Receptors, GABA-A / metabolism*
  • Sensory Gating / genetics
  • Sensory Gating / physiology


  • Disc1 protein, mouse
  • Nerve Tissue Proteins
  • Protein Subunits
  • Receptors, GABA-A