Inhibition of Histone Deacetylase Reinstates Hippocampus-Dependent Long-Term Synaptic Plasticity and Associative Memory in Sleep-Deprived Mice

Author:

Wong Lik-Wei12,Chong Yee Song12,Wong Win Lee Edwin12,Sajikumar Sreedharan12ORCID

Affiliation:

1. Department of Physiology, National University of Singapore, Singapore 117597, Singapore

2. Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore 117 456, Singapore

Abstract

Abstract Sleep plays an important role in the establishment of long-term memory; as such, lack of sleep severely impacts domains of our health including cognitive function. Epigenetic mechanisms regulate gene transcription and protein synthesis, playing a critical role in the modulation of long-term synaptic plasticity and memory. Recent evidences indicate that transcriptional dysregulation as a result of sleep deprivation (SD) may contribute to deficits in plasticity and memory function. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as Vorinostat, a clinically approved drug for human use, has been shown to ameliorate cognitive deficits in several neurological disease models. To further explore the therapeutic effect of SAHA, we have examined its potential role in improving the SD-mediated impairments in long-term plasticity, associative plasticity, and associative memory. Here we show that SAHA preserves long-term plasticity, associative plasticity, and associative memory in SD hippocampus. Furthermore, we find that SAHA prevents SD-mediated epigenetic changes by upregulating histone acetylation, hence preserving the ERK–cAMP-responsive element-binding protein (CREB)/CREB-binding protein–brain-derived neurotrophic factor pathway in the hippocampus. These data demonstrate that modifying epigenetic mechanisms via SAHA can prevent or reverse impairments in long-term plasticity and memory that result from sleep loss. Thus, SAHA could be a potential therapeutic agent in improving SD-related memory deficits.

Funder

National Medical Research Council

Ministry of Education Academic Research Fund Tier 3

Publisher

Oxford University Press (OUP)

Subject

Cellular and Molecular Neuroscience,Cognitive Neuroscience

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