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Updated: Jul 27, 2025
Strategies for Assessing Autistic-Like Behaviors in Mice
Published on: September 20, 2024
Reversal of memory and autism-related phenotypes in
Kleanthi Chalkiadaki1,2, Elpida Statoulla1, Maria Zafeiri1
1Biomedical Research Institute, Foundation for Research and Technology Hellas, Ioannina, Greece.
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.
Insights
Tuberous sclerosis complex (TSC) is linked to autism. Reducing Neuroligin 1 (Nlgn1) expression in TSC mice improved social behaviors and cognitive deficits, offering a potential therapeutic strategy for TSC and related neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by TSC1/TSC2 mutations, often co-occurring with autism spectrum disorder.
- Hyperactivation of the mTORC1 pathway in TSC regulates cap-dependent mRNA translation, contributing to neurodevelopmental phenotypes.
- Previous research linked exaggerated cap-dependent translation to autism-related behaviors and increased Neuroligin 1 (Nlgn1) expression in mice.
Purpose of the Study:
- To investigate the role of Neuroligin 1 (Nlgn1) in the pathophysiology of Tuberous sclerosis complex (TSC).
- To determine if inhibiting Nlgn1 expression can rescue behavioral and cognitive deficits in a mouse model of TSC.
- To explore Nlgn1 reduction as a potential therapeutic strategy for TSC and other neurodevelopmental disorders.
Main Methods:
- Utilized Tsc2+/- mice, a model for Tuberous sclerosis complex (TSC).
- Employed genetic and pharmacological methods to inhibit Neuroligin 1 (Nlgn1) expression.
- Assessed hippocampal long-term depression (mGluR-LTD), contextual discrimination, and social behaviors.
Main Results:
- Demonstrated elevated translation of Nlgn1 mRNA and increased Nlgn1 protein expression in Tsc2+/- mice.
- Observed rescue of impaired hippocampal mGluR-LTD, contextual discrimination, and social behavior deficits following Nlgn1 inhibition.
- Noted that Nlgn1 reduction improved phenotypes without altering the hyperactivated mTORC1 pathway.
Conclusions:
- Reduced Nlgn1 expression represents a novel therapeutic strategy for Tuberous sclerosis complex (TSC).
- Targeting Nlgn1 may offer a viable treatment approach for TSC-associated neurodevelopmental and behavioral deficits.
- This study highlights the potential of Nlgn1 as a therapeutic target for broader neurodevelopmental disorders.
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