Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling
Barrio-Alonso, Estibaliz (Cornell University)
Lituma, Pablo J. (Cornell University)
Notaras, Michael J. (Cornell University)
Albero Gallego, Robert (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Bouchekioua, Youcef (Cornell University)
Wayland, Natalie (Cornell University)
Stankovic, Isidora N. (Cornell University)
Jain, Tanya (Cornell University)
Gao, Sijia (Weill Cornell Medical College (New York, Estats Units d'Amèrica))
Calderon, Diany Paola (Weill Cornell Medical College (New York, Estats Units d'Amèrica))
Castillo, Pablo E. (Albert Einstein College of Medicine (New York, Estats Units d'Amèrica))
Colak, Dilek (Gale & Cornell University)

Data:	2023
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Cell reports, Vol. 42 Núm. 4 (25 2023) , p. 112375, ISSN 2211-1247

DOI: 10.1016/j.celrep.2023.112375
PMID: 37043347

24 p, 6.2 MB

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