Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling
Estibaliz Barrio-Alonso,
Pablo J. Lituma,
Michael J. Notaras,
Robert Albero,
Youcef Bouchekioua,
Natalie Wayland,
Isidora N. Stankovic,
Tanya Jain,
Sijia Gao,
Diany Paola Calderon,
Pablo E. Castillo,
Dilek Colak
Affiliations
Estibaliz Barrio-Alonso
Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
Pablo J. Lituma
Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
Michael J. Notaras
Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
Robert Albero
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Youcef Bouchekioua
Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA
Natalie Wayland
Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
Isidora N. Stankovic
Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
Tanya Jain
Program of Neurosciences, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA
Sijia Gao
Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA
Diany Paola Calderon
Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA
Pablo E. Castillo
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
Dilek Colak
Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA; Gale & Ira Drukier Institute for Children’s Health, Weill Cornell Medical College, Cornell University, New York, NY, USA; Corresponding author
Summary: 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.
