Disc1Point Mutations in Mice Affect Development of the Cerebral Cortex

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.

PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence

“…6B). These observations are in accordance with representative mouse models with genetic mutations in Disc1 that display synaptic deterioration in the adult forebrain (13). Daily administration of FRAX486, but not that of vehicle, between P35 and P60 blocked the exacerbated spine loss during adolescence (Fig.…”

“…In primary neuron culture, prolonged DISC1 knockdown results in the synaptic deterioration (decrease in spine density and size) after transient outgrowth in the pathological course (10). Mouse models that carry two independent Disc1 point mutations show decreased spine density in the glutamatergic synapse in the frontal cortex (13). Synaptic pathology has been frequently observed in brains from patients with schizophrenia (14)(15)(16).…”

Caution When Diagnosing Your Mouse With Schizophrenia: The Use and Misuse of Model Animals for Understanding Psychiatric Disorders

“…The Q31L (127A/T) and L100P (334T/C) mutations produce a number of anatomical and behavioral changes in mice. Disc1-L100P mutant mice have a relative reduction in neuron number, decreased neurogenesis and altered neuron distribution in the frontal cortex (83), and deficits in interneuron migration (84). Disc1 mice carrying a homozygous Q31L mutation are reported to have fewer proliferating cells and disrupted adult neurogenesis (32).…”

The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice

“…Deficits in the balance of excitation and inhibition lead to brain dysfunction and appear to be pivotal in the pathogenesis of major neuropsychiatric disorders, such as schizophrenia and autism (Chao et al, 2010;Kehrer et al, 2008;Uhlhaas and Singer, 2012). Abnormal inhibition of neuronal excitability in neuropsychiatric disorders is often related to abnormalities in the generation of GABAergic neurons (Lee et al, 2011;Levitt et al, 2004;Volk et al, 2000). Identifying the molecular basis underlying the generation of interneurons is therefore expected to augment our understanding of psychiatric disorders.…”