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Disc1 Point Mutations in Mice Affect Development of the Cerebral Cortex

Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 03/2011; 31(9):3197-206. DOI: 10.1523/JNEUROSCI.4219-10.2011
Source: PubMed

ABSTRACT Disrupted-in-Schizophrenia 1 (DISC1) is a strong candidate gene for schizophrenia and other mental disorders. DISC1 regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, and neurotransmitter signaling. Abnormal neuronal morphology and cortical architecture are seen in human postmortem brain from patients with schizophrenia. However, the etiology and development of these histological abnormalities remain unclear. We analyzed the histology of two Disc1 mutant mice with point mutations (Q31L and L100P) and found a relative reduction in neuron number, decreased neurogenesis, and altered neuron distribution compared to wild-type littermates. Frontal cortical neurons have shorter dendrites and decreased surface area and spine density. Overall, the histology of Disc1 mutant mouse cortex is reminiscent of the findings in schizophrenia. These results provide further evidence that Disc1 participates in cortical development, including neurogenesis and neuron migration.

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    • "The combined administration of rolipram and antidepressants to rodents results in increased BDNF expression (Fujimaki et al, 2000) and CA1 spine density (Marchetti et al, 2010). In mouse models of Alzheimer's disease, rolipram restores dendritic spine density (Smith et al, 2009), while Disc1 mutant mice with impaired DISC1-PDE4B binding show alterations in hippocampal spine density (Lee et al, 2011). We therefore sought to examine dendritic spine density in PDE4B Y358C/Y358C mice, focusing on the hippocampus and lateral amygdala. "
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    ABSTRACT: Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4B(Y358C) mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4B(Y358C) mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4B(Y358C) mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4B(Y358C) mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4B(Y358C) mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory.Neuropsychopharmacology accepted article preview online, 14 August 2015. doi:10.1038/npp.2015.240.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2015; DOI:10.1038/npp.2015.240 · 7.83 Impact Factor
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    • "The contrasting effects of the DISC1 mutations we observe in the hippocampus differ from a study utilizing the same line of Disc1 mice to examine how DISC1 affects the embryonic cortex. In that report, both DISC1 mutations led to similar changes in neuronal morphology, spine density, and distribution of neurons in the cortical layers [13], suggesting that proteins within the DISC1 interactome that are affected by these missense mutations are uniquely modulated within select cell populations. To date, more than 30 different proteins have been shown to have specific DISC1 interacting sites, suggesting that the DISC1 mutant proteins likely modulate multiple signalling pathways [39]. "
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    ABSTRACT: Disrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense Disc1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that Disc1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. Disc1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while Disc1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus. Our results demonstrate Disc1 allele specific effects in the adult hippocampus, and suggest that the divergence in behavioural phenotypes may in part stem from changes in specific cell populations in the brain.
    PLoS ONE 10/2014; 9(10):e108088. DOI:10.1371/journal.pone.0108088 · 3.23 Impact Factor
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    • "Another theory is based on the pyramidal interneuron network gamma (PING) model, which suggests that PV-interneurons are recruited by glutamatergic inputs from pyramidal neurons [41]. Previously, misplaced cortical pyramidal neurons and reduced spine densities within layers III and V pyramidal neurons were found in the Disc1-L100P mutants [42]. Consequently, incorrect guidance cues and weakened excitatory drive may lead to less recruitment of PV-interneurons and aberrant cortical lamination [43]. "
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    ABSTRACT: Background Interneuron deficits are one of the most consistent findings in post-mortem studies of schizophrenia patients and are likely important in the cognitive deficits associated with schizophrenia. Disrupted-in-Schizophrenia 1 (DISC1), a strong susceptibility gene for schizophrenia and other mental illnesses, is involved in neurodevelopment, including that of interneurons. However, the mechanism by which DISC1 regulates interneuron development remains unknown. In this study, we analyzed interneuron histology in the Disc1-L100P single point mutation mouse, that was previously shown to have behavioral abnormalities and cortical developmental defects related to schizophrenia. Results We sought to determine whether a Disc1-L100P point mutation in the mouse would alter interneuron density and location. First, we examined interneuron position in the developing mouse cortex during embryonic days 14–16 as an indicator of interneuron tangential migration, and found striking migration deficits in Disc1-L100P mutants. Further analysis of adult brains revealed that the Disc1-L100P mutants have selective alterations of calbindin- and parvalbumin-expressing interneurons in the cortex and hippocampus, decreased GAD67/PV co-localization and mis-positioned interneurons across the neocortex when compared to wild-type littermates. Conclusion Our results are consistent with the anomalies seen in post-mortem schizophrenia studies and other Disc1 mutant mouse models. Future research is required to determine the specific mechanisms underlying these cellular deficits. Overall, these findings provide further evidence that DISC1 participates in interneuron development and add to our understanding of how DISC1 variants can affect susceptibility to psychiatric illness.
    Molecular Brain 04/2013; 6(1):20. DOI:10.1186/1756-6606-6-20 · 4.35 Impact Factor
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