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

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.

Download full-text


Available from: Hanna Jaaro-Peled, Sep 26, 2015
21 Reads
  • Source
    • "Neuron Antioxidants and Adult Prefrontal Function Neuron 83, 1073–1084, September 3, 2014 ª2014 Elsevier Inc. 1081 schizophrenia (Niwa et al., 2010; Tseng et al., 2008 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abnormal development can lead to deficits in adult brain function, a trajectory likely underlying adolescent-onset psychiatric conditions such as schizophrenia. Developmental manipulations yielding adult deficits in rodents provide an opportunity to explore mechanisms involved in a delayed emergence of anomalies driven by developmental alterations. Here we assessed whether oxidative stress during presymptomatic stages causes adult anomalies in rats with a neonatal ventral hippocampal lesion, a developmental rodent model useful for schizophrenia research. Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine prevented the reduction of prefrontal parvalbumin interneuron activity observed in this model, as well as electrophysiological and behavioral deficits relevant to schizophrenia. Adolescent treatment with the glutathione peroxidase mimic ebselen also reversed behavioral deficits in this animal model. These findings suggest that presymptomatic oxidative stress yields abnormal adult brain function in a developmentally compromised brain, and highlight redox modulation as a potential target for early intervention.
    Neuron 08/2014; 83(5). DOI:10.1016/j.neuron.2014.07.028 · 15.05 Impact Factor
  • Source
    • " 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"
    [Show abstract] [Hide abstract]
    ABSTRACT: The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins. Here, we discuss the evidence for a role of DISC1 in synaptic function in the mammalian CNS.
    European Journal of Neuroscience 04/2014; 39(7). DOI:10.1111/ejn.12500 · 3.18 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders.
    Frontiers in Cellular Neuroscience 12/2013; 7:260. DOI:10.3389/fncel.2013.00260 · 4.29 Impact Factor
Show more