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Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits.

Adult brain function and behavior are influenced by neuronal network formation during development. Genetic susceptibility factors for adult psychiatric illnesses, such as Neuregulin-1 and Disrupted-in-Schizophrenia-1 (DISC1), influence adult high brain functions, including cognition and information processing. These factors have roles during neurodevelopment and are likely to cooperate, forming pathways or "signalosomes." Here we report the potential to generate an animal model via in utero gene transfer in order to address an important question of how nonlethal deficits in early development may affect postnatal brain maturation and high brain functions in adulthood, which are impaired in various psychiatric illnesses such as schizophrenia. We show that transient knockdown of DISC1 in the pre- and perinatal stages, specifically in a lineage of pyramidal neurons mainly in the prefrontal cortex, leads to selective abnormalities in postnatal mesocortical dopaminergic maturation and behavioral abnormalities associated with disturbed cortical neurocircuitry after puberty.

Pubmed ID: 20188653

Authors

  • Niwa M
  • Kamiya A
  • Murai R
  • Kubo K
  • Gruber AJ
  • Tomita K
  • Lu L
  • Tomisato S
  • Jaaro-Peled H
  • Seshadri S
  • Hiyama H
  • Huang B
  • Kohda K
  • Noda Y
  • O'Donnell P
  • Nakajima K
  • Sawa A
  • Nabeshima T

Journal

Neuron

Publication Data

February 25, 2010

Associated Grants

  • Agency: NIMH NIH HHS, Id: MH-069853
  • Agency: NIMH NIH HHS, Id: MH-084018
  • Agency: NIMH NIH HHS, Id: MH-088753
  • Agency: NIMH NIH HHS, Id: P20 MH084018
  • Agency: NIMH NIH HHS, Id: P20 MH084018-04
  • Agency: NIMH NIH HHS, Id: R01 MH069853
  • Agency: NIMH NIH HHS, Id: R01 MH069853-08
  • Agency: NIMH NIH HHS, Id: RC1 MH088753
  • Agency: NIMH NIH HHS, Id: RC1 MH088753-02

Mesh Terms

  • Analysis of Variance
  • Animals
  • Antipsychotic Agents
  • Behavior, Animal
  • Cell Differentiation
  • Cell Lineage
  • Chromatography, High Pressure Liquid
  • Clozapine
  • Dopamine
  • Dopamine Agents
  • Electrophysiology
  • Exploratory Behavior
  • Frontal Lobe
  • Gene Transfer Techniques
  • Immunohistochemistry
  • Methamphetamine
  • Mice
  • Microdialysis
  • Motor Activity
  • Nerve Net
  • Nerve Tissue Proteins
  • Neurons
  • RNA Interference
  • Recognition (Psychology)
  • Sensory Gating
  • Spatial Behavior