Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling.
Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling.
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DOI：
10.1016/j.celrep.2023.112375
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发表时间：
2023-04-25
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
生物钟基因对神经元的调节被认为有助于神经元功能的维持，而这些功能最终构成了动物行为的基础。然而，特定的昼夜节律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，我们表明昼夜节律蛋白TIMELESS的表达在哺乳动物海马中表现出昼夜节律性。我们发现TIMELESS是一种染色质结合蛋白，靶向突触可塑性相关基因，如磷酸二酯酶4B （Pde4b）。TIMELESS通过促进Pde4b转录，负调控cAMP信号，调节AMPA受体GluA1功能，影响突触可塑性。成人前脑无时间记忆的条件性缺失会损害小鼠的工作记忆和情境恐惧记忆。这些认知表型伴随着海马Schaffer-collateral突触长期增强的衰减。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，建立了哺乳动物TIMELESS的神经元特异性功能。Barrio-Alonso等人研究了哺乳动物突触可塑性和认知表现中的TIMELESS功能。他们表明，TIMELESS作为一种转录调节剂，影响PDE4B/cAMP水平，从而影响基础神经传递，并最终影响记忆。神经元的无时间性缺失损害了小鼠海马的长期增强，以及工作和情境恐惧记忆。
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. 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.
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影响因子：
2.4
作者：
Campbell SL;van Groen T;Kadish I;Smoot LHM;Bolger GB
通讯作者：
Bolger GB
影响因子：
4.3
作者：
Chauhan R;Chen KF;Kent BA;Crowther DC
通讯作者：
Crowther DC
影响因子：
11
作者：
Delhaye S;Bardoni B
通讯作者：
Bardoni B
DOI：
10.1073/pnas.1118726109
发表时间：
2012-04-03
影响因子：
11.1
作者：
Eckel-Mahan, Kristin L.;Patel, Vishal R.;Sassone-Corsi, Paolo
通讯作者：
Sassone-Corsi, Paolo
影响因子：
56.9
作者：
Bruening, Franziska;Noya, Sara B.;Robles, Maria S.
通讯作者：
Robles, Maria S.