Dataset Information

MTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons.

ABSTRACT: Abnormalities during brain development are thought to cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restricted brain regions of adults, and disruptions of these processes could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specifically in adult-born dentate gyrus (DG) neurons results in increased mTOR signaling, hyperexcitability, and neuronal structure deficits. Disc1 knockdown also resulted in pronounced cognitive and affective deficits, which could be reversed when the affected DG neurons were inactivated. Importantly, reversing increases in mTOR signaling with an FDA-approved inhibitor both prevented and treated these behavioral deficits, even when associated structural deficits were not reversed. Our findings suggest that a component of the affective and cognitive phenotypes in neurodevelopmental disorders may be caused by disruptions in adult-born neurons. Consequently, treatments directed at this cell population may have a significant impact on these phenotypes.

SUBMITTER: Zhou M

PROVIDER: S-EPMC3586374 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Publications

mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons.

Zhou Miou M Li Weidong W Huang Shan S Song Juan J Kim Ju Young JY Tian Xiaoli X Kang Eunchai E Sano Yoshitake Y Liu Cindy C Balaji J J Wu Shumin S Zhou Yu Y Zhou Ying Y Parivash Sherveen N SN Ehninger Dan D He Lin L Song Hongjun H Ming Guo-Li GL Silva Alcino J AJ

Neuron 20130201 4

Abnormalities during brain development are thought to cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restricted brain regions of adults, and disruptions of these processes could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specifically in adult-born dentate gyrus (DG) neurons results in increased mTOR signaling, hyperexcitability, and neuronal ...[more]

PMID: 23439118

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Project description:Recent studies have investigated the effectiveness of aerobic exercise to improve physical and mental health outcomes in schizophrenia; however, few have explicitly explored the impact of aerobic exercise on neural microstructure, which is hypothesized to mediate the behavioral changes observed. Neural microstructure is influenced by numerous genetic factors including DISC1, which is a major molecular scaffold protein that interacts with partners like GSK3β, NDEL1, and PDE4. DISC1 has been shown to play a role in neurogenesis, neuronal migration, neuronal maturation, and synaptic signaling. As with other genetic variants that present an increased risk for disease, mutations of the DISC1 gene have been implicated in the molecular intersection of schizophrenia and numerous other major psychiatric illnesses. This study investigated whether short-term exercise recovers deficits in neural microstructure in a novel genetic Disc1 svΔ2 rat model. Disc1 svΔ2 animals and age- and sex-matched controls were subjected to a treadmill exercise protocol. Subsequent ex-vivo diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) compared neural microstructure in regions of interest (ROI) between sedentary and exercise wild-type animals and between sedentary and exercise Disc1 svΔ2 animals. Short-term exercise uncovered no significant differences in neural microstructure between sedentary and exercise control animals but did lead to significant differences between sedentary and exercise Disc1 svΔ2 animals in neocortex, basal ganglia, corpus callosum, and external capsule, suggesting a positive benefit derived from a short-term exercise regimen. Our findings suggest that Disc1 svΔ2 animals are more sensitive to the effects of short-term exercise and highlight the ameliorating potential of positive treatment interventions such as exercise on neural microstructure in genetic backgrounds of psychiatric disease susceptibility.

Dataset Information

MTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons.

Publications

mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons.

Similar Datasets

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