期刊
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2023.1205112
关键词
tuberous sclerosis; mTOR; translational control; autism; memory
Inhibition of Nlgn1 expression in TSC mouse models can rescue cognitive and social behavior deficits without affecting mTORC1 hyperactivation.
Tuberous sclerosis complex (TSC) is a rare monogenic disorder co-diagnosed with high rates of autism and is caused by loss of function mutations in the TSC1 or TSC2 genes. A key pathway hyperactivated in TSC is the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which regulates cap-dependent mRNA translation. We previously demonstrated that exaggerated cap-dependent translation leads to autism-related phenotypes and increased mRNA translation and protein expression of Neuroligin 1 (Nlgn1) in mice. Inhibition of Nlgn1 expression reversed social behavior deficits in mice with increased cap-dependent translation. Herein, we report elevated translation of Nlgn1 mRNA and an increase in its protein expression. Genetic or pharmacological inhibition of Nlgn1 expression in Tsc2 ( +/- ) mice rescued impaired hippocampal mGluR-LTD, contextual discrimination and social behavior deficits in Tsc2 ( +/- ) mice, without correcting mTORC1 hyperactivation. Thus, we demonstrate that reduction of Nlgn1 expression in Tsc2 ( +/- ) mice is a new therapeutic strategy for TSC and potentially other neurodevelopmental disorders.
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