Histone deacetylase inhibitors restore normal hippocampal synaptic plasticity and seizure threshold in a mouse model of Tuberous Sclerosis Complex

• Published in: Scientific reports Vol. 9; no. 1; p. 5266
• Main Authors: Basu, Trina, O'Riordan, Kenneth J, Schoenike, Barry A, Khan, Nadia N, Wallace, Eli P, Rodriguez, Genesis, Maganti, Rama K, Roopra, Avtar
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 27.03.2019; Nature Publishing Group UK
• Subjects: Acetylation; Acetylation - drug effects; Animals; Autism; Autosomal dominant inheritance; Blotting, Western; Chromatin; Cognitive ability; Convulsions & seizures; Dementia disorders; Electrophysiology; Epilepsy; Genetic disorders; Hereditary diseases; Hippocampal plasticity; Hippocampus; Histone deacetylase; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histone H3; Intracellular signalling; Learning; Male; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Memory; Mice; Mice, Inbred C57BL; Neurological diseases; Phenotypes; Seizures; Seizures - drug therapy; Seizures - metabolism; Signal Transduction - drug effects; Synaptic plasticity; Tuberous sclerosis; Tuberous Sclerosis - drug therapy; Tuberous Sclerosis - metabolism; Tuberous Sclerosis Complex 2; Tuberous Sclerosis Complex 2 Protein - genetics; Tuberous Sclerosis Complex 2 Protein - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-41744-7

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.