Abstracts

Rationale: The mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of cellular growth and protein synthesis-dependent long-term potentiation and depression (LTP and LTD, respectively). Emerging evidence implicates mTOR signaling in the progression of epilepsy. Recently we ve shown that the energy sensor AMP-activated protein kinase (AMPK) can inhibit mTOR signaling to attenuate LTP. This suggests that AMPK activators such as the anti-diabetes drug metformin have therapeutic potential for treating neurological conditions of aberrant plasticity, such as epilepsy. Tuberous Sclerosis patients suffer cognitive impairment and epilepsy that are thought to be driven by hyperactive mTOR signaling and aberrant LTP induction. Therefore, we sought to assess the therapeutic potential of metformin in treating Tuberous Sclerosis. Methods: In a mouse model of Tuberous Sclerosis (TSC2 heterozygous mutants), hippocampal plasticity (LTP and LTD) was characterized using slice electrophysiology in presence and absence of drug. To assess the effects of metformin on learning and memory, metformin was fed to TSC2 mutants and WT controls prior to a spatial learning paradigm. Biochemical evidence for the AMPK-mTOR signaling pathway was conducted to elucidate the mechanism of action for metformin. Results: Here we provide evidence that activation of the metabolic sensor AMPK in TSC2 mutant mice can restore appropriate plasticity and are presently evaluating the effects on learning deficits. This phenotypic rescue is achieved through a TSC1/2 independent inhibition of mTOR signaling by AMPK. Conclusions: Using an animal model of Tuberous Sclerosis, our results suggest that the widely used anti-diabetes drug metformin may have therapeutic potential in restoring cognitive function in TSC patients.