Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation

Author:

Hasegawa Shunsuke,Fukushima Hotaka,Hosoda Hiroshi,Serita Tatsurou,Ishikawa Rie,Rokukawa TomohiroORCID,Kawahara-Miki RyoukaORCID,Zhang Yue,Ohta Miho,Okada Shintaro,Tanimizu Toshiyuki,Josselyn Sheena A.ORCID,Frankland Paul W.ORCID,Kida SatoshiORCID

Abstract

AbstractCognitive 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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