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

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.

Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP

“…No GO terms were enriched in the downregulated RPF group, likely due to the small number of genes. An altered excitatory/inhibitory balance is frequently observed in ASD, and the increased translation of GABA-Arelated proteins may be a compensatory response to the increased hyperexcitability observed in Tsc2 +/− mice [31][32][33][34][35]. Altered translation of mitochondrial membrane proteins is consistent with the role of mTOR-dependent translational control of mitochondrial-related mRNAs and reports of mitochondrial dysfunction in Tsc2-deficient cultured neurons [36,37].…”

Vorinostat corrects cognitive and non-cognitive symptoms in a mouse model of fragile X syndrome

“…injected into mice at 50 mg/kg and 10 mg/kg, respectively. The chosen doses were equivalent or higher than doses used in previous in vivo studies, showing that such treatments are sufficient to improve cognitive functions in mice 16,[20][21][22] . For the examination of object location and passive avoidance memory, drugs were administered 30 min before training.…”

Transcriptional corepressor SIN3A regulates hippocampal synaptic plasticity via Homer1/mGluR5 signaling

“…Indeed, the activation of Src kinase downstream of mGluR5 could potentiate NMDAR signaling and associated signaling networks (42). While we utilized a candidate gene-driven approach to study the effects of Sin3a depletion as it relates to HDAC inhibition, which led us to a specific aspect of mGluR5 signaling and interaction with long-form HOMER1, there are other aspects of mGluR/Homer1 interaction that we did not explore in Sin3aNH mice but that should be investigated in future work, such as mGluR5-LTD, which is impacted by both HDAC inhibition (63) and Homer1b/c depletion (64), as well as agonist-independent signaling through mGluR1/5 induced by Homer1a. It will be both interesting and important to establish fully how Sin3a depletion alters Group I mGluR signaling and what state-specific changes are induced.…”