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Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling.

Estibaliz Barrio-Alonso1, Pablo J Lituma1, Michael J Notaras1

  • 1Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA.

Cell Reports
|April 12, 2023
PubMed
Summary

The circadian protein TIMELESS regulates synaptic plasticity and memory by controlling Pde4b gene expression in the brain. Deleting TIMELESS impairs cognitive functions and hippocampal long-term potentiation.

Keywords:
CP: Molecular biologyCP: NeuroscienceGluA1PDE4BTIMELESScAMPcircadian rhythmshippocampussynaptic plasticity

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Area of Science:

  • Neuroscience
  • Chronobiology
  • Molecular Biology

Background:

  • Circadian clock genes regulate neuronal functions and animal behavior.
  • The specific roles of circadian genes in synaptic plasticity and cognition are not fully understood.

Purpose of the Study:

  • To investigate the role of the circadian protein TIMELESS in the mammalian hippocampus.
  • To elucidate the molecular mechanisms by which TIMELESS influences synaptic plasticity and cognitive function.

Main Methods:

  • Assessed TIMELESS expression rhythmicity in the hippocampus.
  • Identified TIMELESS as a chromatin-bound protein targeting Pde4b.
  • Investigated the effect of TIMELESS on cAMP signaling and AMPA receptor function.
  • Utilized conditional deletion of Timeless in adult forebrain mice to assess cognitive function and synaptic plasticity.

Main Results:

  • TIMELESS expression exhibits circadian rhythmicity in the hippocampus.
  • TIMELESS directly targets and promotes the transcription of Pde4b, a synaptic plasticity-related gene.
  • TIMELESS negatively regulates cAMP signaling, modulating GluA1 function and synaptic plasticity.
  • Conditional deletion of TIMELESS in adult mice impaired working memory, contextual fear memory, and hippocampal long-term potentiation.

Conclusions:

  • TIMELESS plays a crucial neuron-specific role in regulating synaptic plasticity and cognitive function.
  • TIMELESS acts via a mechanism involving Pde4b transcription, cAMP signaling, and AMPA receptor modulation.
  • These findings define a novel molecular pathway linking circadian rhythms to cognitive processes.