Department of Physiology, National University of Singapore, Singapore 117597, Singapore.
Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore 117 456, Singapore.
Cereb Cortex. 2020 Jun 1;30(7):4169-4182. doi: 10.1093/cercor/bhaa041.
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.
睡眠在长期记忆的建立中起着重要作用；因此，睡眠不足会严重影响我们健康的多个领域，包括认知功能。表观遗传机制调节基因转录和蛋白质合成，在调节长期突触可塑性和记忆方面起着关键作用。最近的证据表明，睡眠剥夺（SD）导致的转录失调可能导致可塑性和记忆功能的缺陷。组蛋白去乙酰化酶抑制剂 suberoylanilide hydroxamic acid（SAHA），也称为 Vorinostat，是一种已被批准用于人类的临床药物，已被证明可改善几种神经疾病模型中的认知缺陷。为了进一步探索 SAHA 的治疗效果，我们研究了它在改善 SD 介导的长期可塑性、联想可塑性和联想记忆损伤中的潜在作用。在这里，我们显示 SAHA 可在 SD 海马体中保存长期可塑性、联想可塑性和联想记忆。此外，我们发现 SAHA 通过上调组蛋白乙酰化来防止 SD 介导的表观遗传变化，从而在海马体中保留 ERK-cAMP 反应元件结合蛋白（CREB）/CREB 结合蛋白-脑源性神经营养因子途径。这些数据表明，通过 SAHA 修饰表观遗传机制可以预防或逆转睡眠不足导致的长期可塑性和记忆损伤。因此，SAHA 可能是改善与 SD 相关的记忆缺陷的潜在治疗剂。
