title: Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1.
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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Tochigi, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Taniguchi
authors.affiliation: Basic Sciences Division, Lieber Institute for Brain Development, Baltimore, MD, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Rannals
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: E B
authors.initials: EB
authors.lastname: Merfeld
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Ballinger
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Koga
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, Kanagawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ohtani
authors.affiliation: Neuroscience iMED, AstraZeneca, Cambridge, MA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Gurley
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Sedlak
authors.affiliation: Neuroscience iMED, AstraZeneca, Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cross
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.|Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Moss
authors.affiliation: Neuroscience iMED, AstraZeneca, Cambridge, MA, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Basic Sciences Division, Lieber Institute for Brain Development, Baltimore, MD, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Maher
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kamiya
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018274:Electroporation; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D017397:Prefrontal Cortex / Q000378:metabolism; D021122:Protein Subunits; D017966:Pyramidal Cells / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism*; D055139:Sensory Gating / Q000235:genetics / Q000502:physiology
chemical_list: C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D011963:Receptors, GABA-A