Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, 75005 Paris, France; University Paris-Saclay, CNRS, Paris-Saclay Neuroscience Institute, 91405 Orsay, France.
University Paris-Saclay, CNRS, Paris-Saclay Neuroscience Institute, 91405 Orsay, France.
Neuroscience. 2021 May 21;463:70-85. doi: 10.1016/j.neuroscience.2021.03.004. Epub 2021 Mar 17.
The mitogen-activated protein kinases (MAPK) are major signaling components of intracellular pathways required for memory consolidation. Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2) mediate signal transduction downstream of MAPK. MSKs are activated by Extracellular-signal Regulated Kinase 1/2 (ERK1/2) and p38 MAPK. In turn, they can activate cyclic AMP-response-element-binding protein (CREB), thereby modulating the expression of immediate early genes crucial for the formation of long-term memories. While MSK1 has been previously implicated in certain forms of learning and memory, little is known concerning MSK2. Our goal was to explore the respective contribution of MSK1 and MSK2 in hippocampal synaptic transmission and plasticity and hippocampal-dependent recognition memory. In Msk1- and Msk2-knockout mice, we evaluated object and object-place recognition memory, basal synaptic transmission, paired-pulse facilitation (PPF) and inhibition (PPI), and the capacity to induce and sustain long-term potentiation (LTP) in vivo. We also assessed the level of two proteins downstream in the MAPK/ERK1/2 pathway crucial for long-term memory, CREB and the immediate early gene (IEG) Early growth response 1 (EGR1). Loss of Msk1, but not of Msk2, affected excitatory synaptic transmission at perforant path-to-dentate granule cell synapses, altered short-term presynaptic plasticity, impaired selectively long-term spatial recognition memory, and decreased basal levels of CREB and its activated form. LTP in vivo and LTP-induced CREB phosphorylation and EGR1 expression were unchanged after Msk1 or Msk2 deletion. Our findings demonstrate a dissimilar contribution of MSKs proteins in cognitive processes and suggest that Msk1 loss-of-function only has a deleterious impact on neuronal activity and hippocampal-dependent memory consolidation.
丝裂原活化蛋白激酶（MAPK）是细胞内途径的主要信号成分，这些途径是记忆巩固所必需的。有丝分裂原和应激激活的蛋白激酶 1 和 2（MSK1 和 MSK2）介导 MAPK 下游的信号转导。MSKs 被细胞外信号调节激酶 1/2（ERK1/2）和 p38 MAPK 激活。反过来，它们可以激活环 AMP 反应元件结合蛋白（CREB），从而调节对长时记忆形成至关重要的即时早期基因的表达。虽然先前已经表明 MSK1 参与了某些形式的学习和记忆，但关于 MSK2 的了解甚少。我们的目标是探索 MSK1 和 MSK2 在海马突触传递和可塑性以及海马依赖的识别记忆中的各自贡献。在 Msk1 和 Msk2 敲除小鼠中，我们评估了物体和物体位置识别记忆、基础突触传递、成对脉冲易化（PPF）和抑制（PPI），以及在体内诱导和维持长时程增强（LTP）的能力。我们还评估了 MAPK/ERK1/2 途径中对长时记忆至关重要的两种下游蛋白的水平，即 CREB 和即时早期基因（IEG）早期生长反应 1（EGR1）。Msk1 的缺失而不是 Msk2 的缺失影响了穿通通路到齿状回颗粒细胞突触的兴奋性突触传递，改变了短期突触前可塑性，选择性地损害了长期空间识别记忆，并降低了 CREB 及其激活形式的基础水平。Msk1 或 Msk2 缺失后，体内 LTP 和 LTP 诱导的 CREB 磷酸化和 EGR1 表达没有变化。我们的研究结果表明，MSKs 蛋白在认知过程中具有不同的作用，并表明 Msk1 功能丧失仅对神经元活动和海马依赖的记忆巩固产生有害影响。
