tuberous sclerosis: cognition and autism
Autism is thought to be caused by environmental factors and by many different genes, most of which are still unknown. For example. mutations in the TSC1 and 2 genes are associated with autism and are responsible for Tuberous Sclerosis (TSC). Our mice and patient studies suggested that maternal immune activation may contribute to the risk of autism in TSC.
It is possible that molecular processes triggered by immune activation in pregnant mothers exacerbates 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 Tsc 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 Tsc 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.
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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)