Open AccessHistone deacetylase inhibitors restore normal hippocampal synaptic plasticity and seizure threshold in a mouse model of Tuberous Sclerosis Complex
Author(s) -
Trina Basu,
Kenneth J. O’Riordan,
Barry Schoenike,
Nadia N. Khan,
Eli Wallace,
Genesis Rodriguez,
Rama Maganti,
Avtar Roopra
Publication year - 2019
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-019-41744-7
Subject(s) - histone deacetylase , histone , histone deacetylase 5 , neuroscience , acetylation , synaptic plasticity , histone deacetylase 2 , chromatin , tuberous sclerosis , biology , tsc2 , microbiology and biotechnology , medicine , genetics , signal transduction , psychiatry , pi3k/akt/mtor pathway , receptor , gene
Abnormal synaptic plasticity has been implicated in several neurological disorders including epilepsy, dementia and Autism Spectrum Disorder (ASD). Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder that manifests with seizures, autism, and cognitive deficits. The abnormal intracellular signaling underlying TSC has been the focus of many studies. However, nothing is known about the role of histone modifications in contributing to the neurological manifestations in TSC. Dynamic regulation of chromatin structure via post translational modification of histone tails has been implicated in learning, memory and synaptic plasticity. Histone acetylation and associated gene activation plays a key role in plasticity and so we asked whether histone acetylation might be dysregulated in TSC. In this study, we report a general reduction in hippocampal histone H3 acetylation levels in a mouse model of TSC2. Pharmacological inhibition of Histone Deacetylase (HDAC) activity restores histone H3 acetylation levels and ameliorates the aberrant plasticity in TSC2 +/− mice. We describe a novel seizure phenotype in TSC2 +/− mice that is also normalized with HDAC inhibitors (HDACis). The results from this study suggest an unanticipated role for chromatin modification in TSC and may inform novel therapeutic strategies for TSC patients.