Knockdown of DISC1 by In Utero Gene Transfer Disturbs Postnatal Dopaminergic Maturation in the Frontal Cortex and Leads to Adult Behavioral Deficits

• Published in: Neuron (Cambridge, Mass.) Mass.), 2010-02, Vol.65 (4), p.480-489
• Main Authors: Niwa, Minae, Kamiya, Atsushi, Murai, Rina, Kubo, Ken-ichiro, Gruber, Aaron J., Tomita, Kenji, Lu, Lingling, Tomisato, Shuta, Jaaro-Peled, Hanna, Seshadri, Saurav, Hiyama, Hideki, Huang, Beverly, Kohda, Kazuhisa, Noda, Yukihiro, O'Donnell, Patricio, Nakajima, Kazunori, Sawa, Akira, Nabeshima, Toshitaka
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Antipsychotic Agents - pharmacology; Behavior; Behavior, Animal - drug effects; Behavior, Animal - physiology; Brain; Cell Differentiation - genetics; Cell Lineage - physiology; Chromatography, High Pressure Liquid; Clozapine - pharmacology; Cognition & reasoning; DEVBIO; Dopamine - metabolism; Dopamine Agents - pharmacology; Electrophysiology; Exploratory Behavior - drug effects; Exploratory Behavior - physiology; Frontal Lobe - metabolism; Gene expression; Gene Transfer Techniques; HUMDISEASE; Immunohistochemistry; Mental disorders; Methamphetamine - pharmacology; Mice; Microdialysis; MOLNEURO; Motor Activity - drug effects; Motor Activity - genetics; Nerve Net - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons; Neurons - metabolism; Recognition (Psychology) - drug effects; Recognition (Psychology) - physiology; RNA Interference; Rodents; Sensory Gating - drug effects; Sensory Gating - genetics; Spatial Behavior - drug effects; Spatial Behavior - physiology; Variance analysis
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2010.01.019

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. [Display omitted] ► Generation of an animal model via in utero gene transfer to test brain function ► Disturbance of dopaminergic maturation by knockdown of DISC1 in early development