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

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. [Display omitted] •TIMELESS displays region-specific circadian patterns of expression in the adult mouse brain•TIMELESS is a transcriptional regulator that modulates PDE4B/cAMP levels in hippocampus•Disrupted Timeless enhances GluA1 phosphorylation, spine density, and basal neurotransmission•Timeless deletion attenuates long-term potentiation and contextual fear memory Barrio-Alonso et al. examine mammalian TIMELESS function in synaptic plasticity and cognitive performance. They show that TIMELESS acts as a transcriptional regulator influencing PDE4B/cAMP levels that affect basal neurotransmission and, ultimately, memory. Neuronal deletion of Timeless impairs hippocampal long-term potentiation, as well as working and contextual fear memory in mice.