Reversal of memory and autism-related phenotypes in Tsc2+/- mice via inhibition of Nlgn1.

Frontiers in cell and developmental biology 2023

Chalkiadaki K, Statoulla E, Zafeiri M, Haji N, Lacaille JC, Powell CM, Jafarnejad SM, Khoutorsky A, Gkogkas CG

Abstract

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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