Psychiatric conditions are thought to be caused by interactions of mutations in many different genes and environmental factors. For example, mutations in the TSC1 and 2 genes are associated with autism and are responsible for Tuberous Sclerosis (TSC). Our mice and human studies suggested that pre-natal immune activation may contribute to the risk of autism in TSC. It is possible that molecular processes triggered by immune activation prenatally exacerbate the molecular deficits caused by mutations in the TSC genes.
Additionally, we have also studied in mice the mechanisms responsible for cognitive deficits in TSC. We found that Tsc2 mutant mice have disruptions in protein translation mechanisms that lead to abnormal synaptic plasticity. Remarkably, an FDA approved drug (rapamycin), that targets the biochemical deficits of the Tsc2 mice, reverses the plasticity and cognitive deficits of these mice, even when treatments are started in adults. Currently, there are studies on going to determine if the same treatment is effective in TSC patients.
Our recent findings highlight the role of post-natal immune activation in revealing social phenotypes in males from a mouse model of Tuberous Sclerosis, a genetic disorder associated with high rates of autism. By mining the medical records of more than 3 million children followed from birth, we show that the prevalence of hospitalizations due to infections in males (but not in females) is associated with future development of autism spectrum disorders(PDF). These results were widely covered in the press, including a nice article in the Scientist, as well as another in Spectrum News, another in Express of the UK, etc.
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Lopez-Aranda, M.F., T.K. Silva, M. Zhou, M. Phan, I. Herrera, S. Taloma, R. Mandanas, K. Bach, and A.J. Silva, Role of type I interferon signaling and microglia in the abnormal long-term potentiation and object place recognition deficits of male mice with a mutation of the Tuberous Sclerosis 2 gene Biological Psychiatry:GOS Biological Psychiatry Global Open Science,2022,ISSN 2667-1743, https://doi.org/10.1016/j.bpsgos.2022.03.015.
Manuel F. López-Aranda, Ishanu Chattopadhyay, Gayle M. Boxx, Elizabeth R. Fraley, Tawnie K Silva, Miou Zhou, Miranda Phan, Isaiah Herrera, Sunrae Taloma, Rochelle Mandanas1, Karen Bach, Michael Gandal, Daniel H. Geschwind, Genhong Cheng, Andrey Rzhetsky, Stephanie A. White, Alcino J. Silva. Early post-natal immune activation causes reversible social deficits in a mouse model of TSC: Mechanisms and clinical implications. SCIENCE ADVANCES 2021, Vol 7, Issue 38 DOI: 10.1126/sciadv.abf2073 (PDF).
Ehninger, D., Y. Sano, P.J. de Vries, K. Dies, D. Franz, D.H. Geschwind, M. Kaur, Y.S. Lee, W. Li, J.K. Lowe, J.A. Nakagawa, M. Sahin, K. Smith, V. Whittemore, and A.J. Silva, Gestational immune activation and Tsc2 haploinsufficiency cooperate to disrupt fetal survival and may perturb social behavior in adult mice. Mol Psychiatry, 2010. (PDF)
Ehninger, D. and A.J. Silva, Increased Levels of Anxiety-related Behaviors in a Tsc2 Dominant Negative Transgenic Mouse Model of Tuberous Sclerosis. Behav Genet, 2010.
Ehninger, D., S. Han, C. Shilyansky, Y. Zhou, W. Li, D.J. Kwiatkowski, V. Ramesh, and A.J. Silva, Reversal of learning deficits in a Tsc2(+/-) mouse model of tuberous sclerosis. Nat Med, 2008.(PDF)
Ehninger, D., Li, W, Fox, K, Stryker, MP, and Silva, AJ. Reversing neurodevelopmental disorders in adults. Neuron 2008;60(6):950-60..(PDF)