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: 6.34). 03/2011; 31(9):3197-206. DOI: 10.1523/JNEUROSCI.4219-10.2011
Source: PubMed


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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    • ") 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 · 7.05 Impact Factor
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    • "This chromosomal translocation generates a C-terminal truncated or a fusion protein with DISC1 or a haploinsufficient DISC1 protein, which all cause dysfunctions of DISC1 (Brandon and Sawa, 2011). DISC1 has essential roles in nervous system development, such as proliferation and differentiation of neural progenitor cells (Duan et al, 2007; Ishizuka et al, 2011; Lee et al, 2011), neuronal migration (Kamiya et al, 2005,2008; Young-Pearse et al, 2010), neurite outgrowth (Miyoshi et al, 2003; Ozeki et al, 2003), synapse formation (Hayashi-Takagi et al, 2010; Kvajo et al, 2008; Lee et al, 2011), and mitochondrial trafficking (Atkin et al, 2011; Park et al, 2010). Interestingly, substantial evidence suggests that DISC1 is linked to AD. DISC1 interacts with APP (Young-Pearse et al, 2010), from which Aβ is derived by proteolytic cleavage through a BACE1-dependent mechanism . "
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    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
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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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