Abstracts

Rationale: Tuberous Sclerosis Complex (TSC) is an autosomal dominant, multi-system spectrum disorder that affects approximately 1 in 6,000 people. The disorder is characterized by the formation of benign growths that most commonly develop in the brain, kidney, heart, lungs, eyes and skin (Curatolo, P., 2002; Crino, P.B. 2006 & 2013). Patients with TSC display developmental delays, cognitive defects, and autism. In addition, approximately 80% of patients develop epilepsy within their first year of life. This disease is caused by a loss of function mutation in either the TSC1 or TSC2 genes, resulting in the disinhibition of mammalian Target of Rapamycin (mTOR), a key regulator of cell survival and proliferation, protein synthesis and metabolism (van Slegtenhorst, 1997; Tang, S.J., 2002; Hou, L., 2004). Current treatment involves the modulation of hyperactive mTOR activity, but chronic mTOR inhibition may have adverse effects on patient health (Schindler, C.E., 2014; Carracedo, A., 2008; Kusne, Y., 2014). There is a need to find a TSC specific treatment that does not present with harmful side effects. Methods: Acute hippocampal slices from adult male heterozygous TSC2 mutant mice (TSC2+/-) display abnormal long term potentiation (LTP) and long term depression (LTD) (Potter, W., 2013). A 1X theta burst stimulation elicits short term potentiation in adult male wild type (WT) hippocampi, but this paradigm induces LTP in hippocampi obtained from gender and age matched TSC2+/- mice. In contrast to adult male WT mice, the TSC2+/- mice display a rapamycin insensitive form of metabotropic glutamate receptor (mGluR) mediated LTD. Results: A whole genome expression analysis of cortical samples resected from human TSC and non-TSC patients suggests that epigenetic mechanisms may drive the observed synaptic plasticity alterations upon loss of a TSC allele. We find that the modulation of chromatin structure through the pharmacological inhibition of histone deacetylation or methylation restores normal synaptic plasticity in adult male TSC2+/- mice. Conclusions: This study is the first to describe epigenetic mechanisms influencing synaptic plasticity alterations in TSC and may unearth a novel therapeutic option to treat the neurological manifestations in TSC patients. Funding: NTP(T32 GM007507), R21 NS093364, R21 NS095187  RO1 NS065067, Lily’s Fund-Spark Award, CURE.