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.
Niwa
Minae
M
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Kamiya
Atsushi
A
Murai
Rina
R
Kubo
Ken-ichiro
K
Gruber
Aaron J
AJ
Tomita
Kenji
K
Lu
Lingling
L
Tomisato
Shuta
S
Jaaro-Peled
Hanna
H
Seshadri
Saurav
S
Hiyama
Hideki
H
Huang
Beverly
B
Kohda
Kazuhisa
K
Noda
Yukihiro
Y
O'Donnell
Patricio
P
Nakajima
Kazunori
K
Sawa
Akira
A
Nabeshima
Toshitaka
T
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004594:Electrophysiology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005625:Frontal Lobe / Q000378:metabolism*; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009415:Nerve Net / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D055139:Sensory Gating / Q000187:drug effects / Q000235:genetics; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; C498794:Disc1 protein, mouse; D015259:Dopamine Agents; D009419:Nerve Tissue Proteins; D008694:Methamphetamine; D003024:Clozapine; D004298:Dopamine