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

Nat Commun. 2019 Dec 18;10(1):5766. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • Circadian Clocks / physiology*
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dopamine / metabolism
  • Female
  • Gene Knock-In Techniques
  • Hippocampus / metabolism*
  • Male
  • Maze Learning
  • Mental Recall / physiology*
  • Mice
  • Mice, Transgenic
  • Models, Animal
  • Phosphorylation / physiology
  • Receptors, AMPA / metabolism*

Substances

  • ARNTL Transcription Factors
  • Bmal1 protein, mouse
  • Receptors, AMPA
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • glutamate receptor ionotropic, AMPA 1
  • Dopamine