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

Trina Basu,Nadia N Khan,Avtar Roopra,Barry A Schoenike,Rama K Maganti,Eli P Wallace,Genesis Rodriguez,Kenneth J O’Riordan

doi:10.1038/s41598-019-41744-7

Trina Basu, Nadia N Khan + Show 6 more

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https://doi.org/10.1038/s41598-019-41744-7

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Journal: Scientific Reports	Publication Date: Mar 27, 2019
Citations: 27	License type: open-access

Affiliation: University of Wisconsin–Madison

Abstract

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.

Highlights

Synaptic plasticity underlies mechanisms for encoding new information and forming long term memory in the mammalian hippocampus[1,2,3,4]
We show that pharmacological attenuation of Histone Deacetylase (HDAC) activity in TSC2+/− mice restores synaptic plasticity and normalizes a novel seizure threshold phenotype to resemble a wild type (WT) response
We provide for the first time, evidence suggesting that the TSC2+/− mouse exhibits an imbalance of HDAC and Histone Acetyltransferase (HAT) activity that is driving abnormal synaptic plasticity

Summary

Introduction

Synaptic plasticity underlies mechanisms for encoding new information and forming long term memory in the mammalian hippocampus[1,2,3,4]. Aberrations in acquiring or maintaining synaptic plasticity have been linked to cognitive deficits, intellectual disability, epilepsy and autism spectrum disorder (ASD)[5,6,7,8]. The TSC1 (hamartin) and TSC2 (tuberin) proteins heterodimerize to form a GTPase activating protein (GAP) complex which inhibits the mammalian Target of Rapamycin Complex 1 (mTORC1) via negative regulation of the GTP binding protein, Rho enriched in the brain (Rheb)[13]. MTORC1 signaling pathway is a critical kinase hub that regulates post-synaptic protein translation to influence synaptogenesis, dendritic and axonal growth, and activity dependent synaptic plasticity[11,14,15,16,17]. Www.nature.com/scientificreports and aberrant hippocampal synaptic plasticity, impairments in learning and memory, epilepsy, and autism-like behavioral phenotypes[18,19,20,21,22]

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