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

Minae Niwa; Atsushi Kamiya; Rina Murai; Ken-ichiro Kubo; Aaron J Gruber; Kenji Tomita; Lingling Lu; Shuta Tomisato; Hanna Jaaro-Peled; Saurav Seshadri; Hideki Hiyama; Beverly Huang; Kazuhisa Kohda; Yukihiro Noda; Patricio O'Donnell; Kazunori Nakajima; Akira Sawa; Toshitaka Nabeshima

doi:10.1016/j.neuron.2010.01.019

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

Neuron. 2010 Feb 25;65(4):480-9. doi: 10.1016/j.neuron.2010.01.019.

Authors

Minae Niwa¹, Atsushi Kamiya, Rina Murai, Ken-ichiro Kubo, Aaron J Gruber, Kenji Tomita, Lingling Lu, Shuta Tomisato, Hanna Jaaro-Peled, Saurav Seshadri, Hideki Hiyama, Beverly Huang, Kazuhisa Kohda, Yukihiro Noda, Patricio O'Donnell, Kazunori Nakajima, Akira Sawa, Toshitaka Nabeshima

Affiliation

¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Abstract

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.

Publication types

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

MeSH terms

Analysis of Variance
Animals
Antipsychotic Agents / pharmacology
Behavior, Animal / drug effects
Behavior, Animal / physiology*
Cell Differentiation / genetics
Cell Lineage / physiology
Chromatography, High Pressure Liquid
Clozapine / pharmacology
Dopamine / metabolism*
Dopamine Agents / pharmacology
Electrophysiology
Exploratory Behavior / drug effects
Exploratory Behavior / physiology
Frontal Lobe / metabolism*
Gene Transfer Techniques
Immunohistochemistry
Methamphetamine / pharmacology
Mice
Microdialysis
Motor Activity / drug effects
Motor Activity / genetics
Nerve Net / metabolism
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
Neurons / metabolism
RNA Interference
Recognition, Psychology / drug effects
Recognition, Psychology / physiology
Sensory Gating / drug effects
Sensory Gating / genetics
Spatial Behavior / drug effects
Spatial Behavior / physiology

Substances

Antipsychotic Agents
Disc1 protein, mouse
Dopamine Agents
Nerve Tissue Proteins
Methamphetamine
Clozapine
Dopamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding