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生物钟蛋白 TIMELESS 通过调节 cAMP 信号调节突触功能和记忆。

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

机构信息

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

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

出版信息

Cell Rep. 2023 Apr 25;42(4):112375. doi: 10.1016/j.celrep.2023.112375. Epub 2023 Apr 11.

DOI:10.1016/j.celrep.2023.112375
PMID:37043347
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10564971/
Abstract

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.

摘要

生物钟基因对神经元的调节被认为有助于维持神经元功能，而神经元功能最终是动物行为的基础。然而，特定的生物钟基因对控制突触可塑性和认知功能的细胞和分子机制的影响仍然难以捉摸。在这里，我们表明，生物钟蛋白 TIMELESS 在哺乳动物海马体中表现出昼夜节律性。我们将 TIMELESS 鉴定为一种与染色质结合的蛋白质，它靶向与突触可塑性相关的基因，如磷酸二酯酶 4B（Pde4b）。通过促进 Pde4b 的转录，TIMELESS 负调控 cAMP 信号转导，以调节 AMPA 受体 GluA1 的功能并影响突触可塑性。成年大脑中 Timeless 的条件性缺失会损害小鼠的工作记忆和情境性恐惧记忆。这些认知表型伴随着海马体 Schaffer 侧枝长时程增强的减弱。总之，这些数据通过定义调节突触可塑性和认知功能的机制，确立了哺乳动物 TIMELESS 的神经元特异性功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/28f8ff3d4668/nihms-1895599-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/7812427eb76f/nihms-1895599-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/a56ca68e1736/nihms-1895599-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/dd9c79b4768b/nihms-1895599-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/53cc3369a9d6/nihms-1895599-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/0ab5273975b6/nihms-1895599-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/0ca45b2eee85/nihms-1895599-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/28f8ff3d4668/nihms-1895599-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/7812427eb76f/nihms-1895599-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/a56ca68e1736/nihms-1895599-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/dd9c79b4768b/nihms-1895599-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/53cc3369a9d6/nihms-1895599-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/0ab5273975b6/nihms-1895599-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/0ca45b2eee85/nihms-1895599-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3081/10564971/28f8ff3d4668/nihms-1895599-f0008.jpg

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