School of Life Sciences, University of Warwick, Coventry, CV4 7AL, UK.
Division of Cell Signalling and Immunology, Wellcome Trust Building, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Neuropharmacology. 2022 Nov 15;219:109237. doi: 10.1016/j.neuropharm.2022.109237. Epub 2022 Aug 30.
The transcription factor cAMP response element-binding protein (CREB) is widely regarded as orchestrating the genomic response that underpins a range of physiological functions in the central nervous system, including learning and memory. Of the means by which CREB can be regulated, emphasis has been placed on the phosphorylation of a key serine residue, S133, in the CREB protein, which is required for CREB-mediated transcriptional activation in response to a variety of activity-dependent stimuli. Understanding the role of CREB S133 has been complicated by molecular genetic techniques relying on over-expression of either dominant negative or activating transgenes that may distort the physiological role of endogenous CREB. A more elegant recent approach targeting S133 in the endogenous CREB gene has yielded a mouse with constitutive replacement of this residue with alanine (S133A), but has generated results (no behavioural phenotype and no effect on gene transcription) at odds with contemporary views as to the role of CREB S133, and which may reflect compensatory changes associated with the constitutive mutation. To avoid this potential complication, we generated a post-natal and forebrain-specific CREB S133A mutant in which the expression of the mutation was under the control of CaMKIIα promoter. Using male and female mice we show that CREB S133 is necessary for spatial cognitive flexibility, the regulation of basal synaptic transmission, and for the expression of long-term potentiation (LTP) in hippocampal area CA1. These data point to the importance of CREB S133 in neuronal function, synaptic plasticity and cognition in the mammalian brain.
转录因子 cAMP 反应元件结合蛋白（CREB）被广泛认为是协调基因组反应的关键，这种反应支持中枢神经系统的一系列生理功能，包括学习和记忆。在调节 CREB 的各种方法中，重点放在 CREB 蛋白中关键丝氨酸残基 S133 的磷酸化上，该残基是 CREB 介导的转录激活所必需的，以响应各种活性依赖性刺激。理解 CREB S133 的作用受到依赖于过表达显性负或激活转基因的分子遗传技术的限制，这些技术可能会扭曲内源性 CREB 的生理作用。最近一种针对内源性 CREB 基因中 S133 的更优雅的方法产生了一种老鼠，其 S133 残基被丙氨酸（S133A）取代，但是产生的结果（无行为表型且对基因转录没有影响）与当代关于 CREB S133 作用的观点不一致，这可能反映了与组成型突变相关的代偿性变化。为了避免这种潜在的复杂性，我们在出生后和前脑中特异性地产生了 CREB S133A 突变体，该突变体的表达受 CaMKIIα 启动子的控制。使用雄性和雌性小鼠，我们表明 CREB S133 对于空间认知灵活性、基础突触传递的调节以及海马区 CA1 中长时程增强（LTP）的表达是必需的。这些数据表明 CREB S133 在哺乳动物大脑中的神经元功能、突触可塑性和认知中具有重要意义。
