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

Shunsuke Hasegawa,Toshiyuki Tanimizu,Shintaro Okada,Hiroshi Hosoda,Ryouka Kawahara-Miki,Yue Zhang,Paul W Frankland,Miho Ohta,Tomohiro Rokukawa,Rie Ishikawa,Sheena A Josselyn,Hotaka Fukushima,Satoshi Kida,Tatsurou Serita

doi:10.1038/s41467-019-13554-y

Abstract

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.

Highlights

Cognitive performance in people varies according to time-of-day, with memory retrieval declining in the late afternoon-early evening
Our findings suggest that phosphorylation of GluA1 Serine 845 (S845) by protein kinase A (PKA) is required for enhancement of memory retrieval and that reduced phosphorylation of S845 by lowered activity of BMAL1 in the hippocampus impairs retrieval
Circadian rhythm of gene expression controlled by transcription factor BMAL1/CLOCK is observed in the suprachiasmatic nuclei (SCN), thought to be the master circadian clock in mammals[1,2,4,5], and in non-SCN regions[5,6,7]

Summary

Introduction

Cognitive performance in people varies according to time-of-day, with memory retrieval declining in the late afternoon-early evening. 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 DopaminecAMP signaling in dnBMAL1 mice. There is increasing evidence that molecular clocks in these extra-SCN regions exert autonomous circadian regulation of tissue-specific functions[1,8,9,10,11,12,13,14] It has been known since experiments by Ebbinghaus (1885) that time-of-day influences cognitive performance and memory (wherein performance declines in the late morning to early evening15), the mechanisms underlying this effect are not well understood[16,17,18,19]. We investigated the local role of this molecular clock in the hippocampus in memory processes using mice

Methods

Results

Conclusion