Abstracts

Rationale: Tuberous Sclerosis Complex (TSC) is one of the most common inherited forms of epilepsy and is caused by a mutation in either TSC1 or TSC2 genes leading to heightened mammalian target of Rapamycin (mTOR) activity (van Slegtenhorst, 1997). Mammalian TOR is a protein kinase that regulates activity dependent translation of dendritic proteins required for synaptic plasticity in the hippocampus. Persistent mTOR activation in TSC leads to heightened dendritic protein synthesis and aberrant synaptic plasticity deficits (Tang, S.J., 2002; Hou, L, 2004). It is imperative to find a novel avenue of treatment for TSC patients, and epilepsy patients in general, that suppresses epileptiform activity without harmful side effects. Methods: Epileptiform activity can be induced in mouse hippocampal slices through prolonged incubation with the group 1 metabotropic glutamate receptor (mGluR) agonist, DHPG. Through electrophysiology recordings from the CA3 stratum pyramidale region of the hippocampus, we find that adult heterozygous TSC2 mutants (TSC2+/-) have greater ictal-like activity (burst durations lasting more than 2 seconds with greater than 2 Hz of intraburst frequency) and more long duration burst activity compared to wild type (WT) mice (Potter, W.B., 2013). It is also known that adult TSC2+/- mice have aberrant synaptic plasticity compared to adult WT mice. Whereas a 1X theta burst stimulation induces short term potentiation in adult WT mice, this paradigm is enough to abnormally induce long term potentiation in adult TSC2+/- mice. In addition, unlike adult WT mice, adult TSC2+/- mice display rapamycin insensitive long term depression. Results: A whole genome expression analysis of cortical samples from TSC and non-TSC patients indicated that a majority of gene expression changes between the two populations may be epigenetically regulated. Using drugs that alter chromatin structures through histone deacetylation and histone demethylation, we found that the epileptiform activity and aberrant synaptic plasticity characteristic of TSC2+/- mice was ameliorated.Conclusions: Not only is our study the first to show that epigenetic mechanisms influence the epileptogenesis in TSC, but it also uncovers a potential treatment option for TSC patients through the use of clinically available epigenetic modifying drugs.