Ayhan Y, Abazyan B, Nomura J, Kim R, Ladenheim B, Krasnova IN et al. Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders. Mol Psychiatry 16: 293-306

Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Molecular Psychiatry (Impact Factor: 14.5). 03/2011; 16(3):293-306. DOI: 10.1038/mp.2009.144
Source: PubMed


Strong genetic evidence implicates mutations and polymorphisms in the gene Disrupted-In-Schizophrenia-1 (DISC1) as risk factors for both schizophrenia and mood disorders. Recent studies have shown that DISC1 has important functions in both brain development and adult brain function. We have described earlier a transgenic mouse model of inducible expression of mutant human DISC1 (hDISC1) that acts in a dominant-negative manner to induce the marked neurobehavioral abnormalities. To gain insight into the roles of DISC1 at various stages of neurodevelopment, we examined the effects of mutant hDISC1 expressed during (1) only prenatal period, (2) only postnatal period, or (3) both periods. All periods of expression similarly led to decreased levels of cortical dopamine (DA) and fewer parvalbumin-positive neurons in the cortex. Combined prenatal and postnatal expression produced increased aggression and enhanced response to psychostimulants in male mice along with increased linear density of dendritic spines on neurons of the dentate gyrus of the hippocampus, and lower levels of endogenous DISC1 and LIS1. Prenatal expression only resulted in smaller brain volume, whereas selective postnatal expression gave rise to decreased social behavior in male mice and depression-like responses in female mice as well as enlarged lateral ventricles and decreased DA content in the hippocampus of female mice, and decreased level of endogenous DISC1. Our data show that mutant hDISC1 exerts differential effects on neurobehavioral phenotypes, depending on the stage of development at which the protein is expressed. The multiple and diverse abnormalities detected in mutant DISC1 mice are reminiscent of findings in major mental diseases.

Download full-text


Available from: Jun Nomura, Oct 14, 2015
1 Follower
24 Reads
  • Source
    • "For the adult behavioral assessment, novelty-induced activity was evaluated in open field test for 30 min on PND 60 as previously described (Ayhan et al., 2011). "
    Dataset: BBIpaper
  • Source
    • "Moreover, several neuropsychiatric symptoms, such as abnormalities in emotionality/activity, social interactions, and sensomotor abilities are commonly detected in AD patients (Lyketsos et al, 2011). Deficits in working memory and social interactions that have been described for DISC1 mutant mice (Ayhan et al, 2011; Koike et al, 2006; Pletnikov et al, 2008) are also observed in BACE1 knock-in transgenic mice (Plucinska et al, 2014). Thus, the present study may suggest a possibility that decreased levels of DISC1 may account for the neuropsychiatric symptoms in AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Disrupted-in-schizophrenia-1 (DISC1) is a genetic risk factor for a wide range of major mental disorders including schizophrenia, major depression and bipolar disorders. Recent reports suggest a potential role of DISC1 in the pathogenesis of Alzheimer's disease (AD), by referring to an interaction between DISC1 and amyloid precursor protein (APP), and to an association of a single nucleotide polymorphism in a DISC1 intron and late onset of AD. However, the function of DISC1 in AD remains unknown. In this study, decreased levels of DISC1 were observed in the cortex and hippocampus of 8-month-old APP/PS1 transgenic mice, an animal model of AD. Overexpression of DISC1 reduced, while knockdown of DISC1 increased protein levels, but not mRNA levels of β-site APP-Cleaving Enzyme 1 (BACE1), a key enzyme in amyloid-β (Aβ) generation. Reduction of BACE1 protein levels by overexpression of DISC1 was accompanied by an accelerating decline rate of BACE1, and was blocked by the lysosomal inhibitor chloroquine, rather than proteasome inhibitor MG-132. Moreover, overexpression of DISC1 in the hippocampus with an adeno-associated virus reduced the levels of BACE1, soluble Aβ40/42, amyloid plaque density, and rescued cognitive deficits of APP/PS1 transgenic mice. These results indicate that DISC1 attenuates amyloid-β generation and cognitive deficits of APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1. Our findings provide new insights into the role of DISC1 in AD pathogenesis and link a potential function of DISC1 to the psychiatric symptoms of AD.Neuropsychopharmacology accepted article preview online, 11 June 2015. doi:10.1038/npp.2015.164.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.164 · 7.05 Impact Factor
  • Source
    • "We recently provided in vitro evidence that during embryonic development DISC1 is a necessary component for the correct tangential migration of cortical interneurons from the medial ganglionic eminence (MGE) to their target regions in the cortex (Steinecke et al., 2012). This is in accordance with previous studies which found a reduced number of parvalbumin-positive interneurons in a mouse line that expresses the truncated human DISC1, as in the Scottish pedigree (Pletnikov et al., 2008; Ayhan et al., 2011). In the present study we first demonstrate the importance of DISC1 during tangential migration in the intact brain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Disrupted-in-Schizophrenia 1 (DISC1) is a risk gene for a spectrum of major mental disorders. It has been shown to regulate radial migration as well as dendritic arborization during neurodevelopment and corticogenesis. In a previous study we demonstrated through in vitro experiments that DISC1 also controls the tangential migration of cortical interneurons originating from the medial ganglionic eminence (MGE). Here we first show that DISC1 is necessary for the proper tangential migration of cortical interneurons in the intact brain. Expression of EGFP under the Lhx6 promotor allowed us to analyze exclusively interneurons transfected in the MGE after in utero electroporation. After 3 days in utero, DISC1 deficient interneurons displayed prolonged leading processes and, compared to control, fewer neurons reached the cortex. Time-lapse video microscopy of cortical feeder-layers revealed a decreased migration velocity due to a reduction of soma translocations. Immunostainings indicated that DISC1 is co-localized with F-actin in the growth cone-like structure of the leading process. DISC1 knockdown reduced F-actin levels whereas the overall actin level was not altered. Moreover, DISC1 knockdown also decreased levels of phosphorylated Girdin, which cross-links F-actin, as well as the Girdin-activator pAkt. In contrast, using time-lapse video microscopy of fluorescence-tagged tubulin and EB3 in fibroblasts, we found no effects on microtubule polymerization when DISC1 was reduced. However, DISC1 affected the acetylation of microtubules in the leading processes of MGE-derived cortical interneurons. Together, our results provide a mechanism how DISC1 might contribute to interneuron migration thereby explaining the reduced number of specific classes of cortical interneurons in some DISC1 mouse models.
    Frontiers in Cellular Neuroscience 07/2014; 8:190. DOI:10.3389/fncel.2014.00190 · 4.29 Impact Factor
Show more