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Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling
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DOI：10.1016/j.celrep.2023.112375.png)
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Abstract
En 中文
The regulation of neurons by circadian clock genes is thought to contribute to the maintenance of neuronal functions that ultimately underlie animal behavior. However, the impact of specific circadian genes on cellular and molecular mechanisms controlling synaptic plasticity and cognitive function remains elusive. Here, we show that the expression of the circadian protein TIMELESS displays circadian rhythmicity in the mammalian hippocampus. We identify TIMELESS as a chromatin-bound protein that targets synaptic-plasticity-related genes such as phosphodiesterase 4B (Pde4b). By promoting Pde4b transcription, TIMELESS negatively regulates cAMP signaling to modulate AMPA receptor GluA1 function and influence synaptic plasticity. Conditional deletion of Timeless in the adult forebrain impairs working and contextual fear memory in mice. These cognitive phenotypes were accompanied by attenuation of hippocampal Schaffer-collateral synapse long-term potentiation. Together, these data establish a neuron-specific function of mammalian TIMELESS by defining a mechanism that regulates synaptic plasticity and cognitive function.
Keywords:
LONG-TERM POTENTIATION
CLOCK GENE-EXPRESSION
AMPA RECEPTOR PHOSPHORYLATION
PKA PHOSPHORYLATION
DROSOPHILA-TIMELESS
PERISYNAPTIC SITES
MAMMALIAN TIMELESS
MOLECULAR ANALYSIS
PREFRONTAL CORTEX
TRAFFICKING
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