Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation.,Nature Communications

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Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation.
Nature Communications ( IF 14.7 ) Pub Date : 2019-12-18 , DOI: 10.1038/s41467-019-13554-y
Shunsuke Hasegawa _{1,

2} , Hotaka Fukushima _{1,

2} , Hiroshi Hosoda ₁ , Tatsurou Serita ₁ , Rie Ishikawa _{1,

3} , Tomohiro Rokukawa ₁ , Ryouka Kawahara-Miki ₄ , Yue Zhang _{1,

2} , Miho Ohta ₁ , Shintaro Okada ₁ , Toshiyuki Tanimizu ₁ , Sheena A Josselyn _{5,

6} , Paul W Frankland _{5,

6} , Satoshi Kida _{1,

2,

3}

Affiliation

Cognitive performance in people varies according to time-of-day, with memory retrieval declining in the late afternoon-early evening. However, functional roles of local brain circadian clocks in memory performance remains unclear. Here, we show that hippocampal clock controlled by the circadian-dependent transcription factor BMAL1 regulates time-of-day retrieval profile. Inducible transgenic dominant negative BMAL1 (dnBMAL1) expression in mouse forebrain or hippocampus disrupted retrieval of hippocampal memories at Zeitgeber Time 8-12, independently of retention delay, encoding time and Zeitgeber entrainment cue. This altered retrieval profile was associated with downregulation of hippocampal Dopamine-cAMP signaling in dnBMAL1 mice. These changes included decreases in Dopamine Receptors (D1-R and D5-R) and GluA1-S845 phosphorylation by PKA. Consistently, pharmacological activation of cAMP-signals or D1/5Rs rescued impaired retrieval in dnBMAL1 mice. Importantly, GluA1 S845A knock-in mice showed similar retrieval deficits with dnBMAL1 mice. Our findings suggest mechanisms underlying regulation of retrieval by hippocampal clock through D1/5R-cAMP-PKA-mediated GluA1 phosphorylation.

中文翻译：

海马时钟通过多巴胺和 PKA 诱导的 GluA1 磷酸化调节记忆检索。

人们的认知表现根据一天中的不同时间而变化，记忆检索在下午晚些时候到傍晚早些时候会下降。然而，局部大脑生物钟在记忆表现中的功能作用仍不清楚。在这里，我们展示了由昼夜节律依赖性转录因子 BMAL1 控制的海马时钟调节一天中的时间检索特征。小鼠前脑或海马中诱导性转基因显性失活 BMAL1 (dnBMAL1) 表达破坏了 Zeitgeber 时间 8-12 时海马记忆的检索，与保留延迟、编码时间和 Zeitgeber 夹带提示无关。这种改变的检索特征与 dnBMAL1 小鼠海马多巴胺-cAMP 信号传导的下调有关。这些变化包括多巴胺受体（D1-R 和 D5-R）的减少以及 PKA 磷酸化 GluA1-S845 的减少。一致地，cAMP 信号或 D1/5R 的药理激活可挽救 dnBMAL1 小鼠中受损的检索。重要的是，GluA1 S845A 敲入小鼠表现出与 dnBMAL1 小鼠相似的检索缺陷。我们的研究结果表明海马时钟通过 D1/5R-cAMP-PKA 介导的 GluA1 磷酸化调节检索的潜在机制。

更新日期：2019-12-19

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