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

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Neuron (Impact Factor: 15.05). 02/2010; 65(4):480-9. DOI: 10.1016/j.neuron.2010.01.019
Source: PubMed


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.

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    • " or membrane potential . However , dopamine D2er - gic modulation of electrically evoked excitatory postsynaptic potentials in these deep layer neurons is strongly attenuated when DISC1 is knocked down . This observation is thought to be related to the disturbed dopaminergic innervation of this cortical area pro - duced by the knockdown of DISC1 ( Niwa et al . , 2010 ) . DISC1 levels are unquestionably high in postsynaptic elements . Additionally , a number of DISC1 binding partners also show promi - nent postsynaptic localisation and possess known postsynaptic roles . Consequently , investigations of DISC1 neurophysiology at synapses have tended to concentrate on postsynaptic functionality . Howeve"
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    • "The translocation in the gene disrupted in schizophrenia-1 (DISC-1) was originally found in a large Scottish family with abnormally high rates of neuropsychiatric disease (Millar et al., 2001). Interestingly, knockdown of DISC-1 in animal models causes altered DAergic maturation and behavioral changes associated with altered prefrontal cortex circuitry, suggesting a role for DA in DISC-1 associated neuropsychiatric disease (Niwa et al., 2010). Association studies implicate the A1 allele of the Taq1 polymorphism of DRD2 in the development of Tourette’s syndrome, ADHD, autism, PTSD, and alcoholism (Comings et al., 1991). "
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