Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Barcelona, Spain.
Institut de Neurociències, Department de Bioquímica i Biologia Molecular; and the.
Biol Psychiatry. 2017 Jan 15;81(2):111-123. doi: 10.1016/j.biopsych.2016.06.025. Epub 2016 Jul 11.
Associative memory impairment is an early clinical feature of dementia patients, but the molecular and cellular mechanisms underlying these deficits are largely unknown. In this study, we investigated the functional regulation of the cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) by associative learning in physiological and neurodegenerative conditions.
We evaluated the activation of CRTC1 in the hippocampus of control mice and mice lacking the Alzheimer's disease-linked presenilin genes (presenilin conditional double knockout [PS cDKO]) after one-trial contextual fear conditioning by using biochemical, immunohistochemical, and gene expression analyses. PS cDKO mice display classical features of neurodegeneration occurring in Alzheimer's disease including age-dependent cortical atrophy, neuron loss, dendritic degeneration, and memory deficits.
Context-associative learning, but not single context or unconditioned stimuli, induces rapid dephosphorylation (Ser151) and translocation of CRTC1 from the cytosol/dendrites to the nucleus of hippocampal neurons in the mouse brain. Accordingly, context-associative learning induces differential CRTC1-dependent transcription of c-fos and the nuclear receptor subfamily 4 (Nr4a) genes Nr4a1-3 in the hippocampus through a mechanism that involves CRTC1 recruitment to CRE promoters. Deregulation of CRTC1 dephosphorylation, nuclear translocation, and transcriptional function are associated with long-term contextual memory deficits in PS cDKO mice. Importantly, CRTC1 gene therapy in the hippocampus ameliorates context memory and transcriptional deficits and dendritic degeneration despite ongoing cortical degeneration in this neurodegeneration mouse model.
These findings reveal a critical role of CRTC1 in the hippocampus during associative memory, and provide evidence that CRTC1 deregulation underlies memory deficits during neurodegeneration.
联想记忆损伤是痴呆症患者的早期临床特征，但这些缺陷背后的分子和细胞机制在很大程度上尚不清楚。在这项研究中，我们研究了在生理和神经退行性条件下联想学习对环磷酸腺苷反应元件结合蛋白（CREB）调节的转录共激活因子 1（CRTC1）的功能调节。
我们通过生化、免疫组织化学和基因表达分析，评估了单次情景恐惧条件后，控制小鼠和缺乏阿尔茨海默病相关早老素基因的小鼠（早老素条件性双敲除[PS cDKO]）海马中 CRTC1 的激活情况。PS cDKO 小鼠表现出包括皮质萎缩、神经元丧失、树突退化和记忆缺陷在内的与阿尔茨海默病相关的经典神经退行性特征。
情景联想学习而不是单一情景或非条件刺激，可诱导 CRTC1 从细胞质/树突快速去磷酸化（Ser151）和转位到小鼠大脑海马神经元的核内。因此，情景联想学习通过涉及 CRTC1 募集到 CRE 启动子的机制，诱导 CRTC1 依赖性 c-fos 和核受体亚家族 4（Nr4a）基因 Nr4a1-3 的差异转录。CRTC1 去磷酸化、核易位和转录功能的失调与 PS cDKO 小鼠的长期情景记忆缺陷有关。重要的是，CRTC1 基因治疗可改善该神经退行性小鼠模型中海马的情景记忆和转录缺陷以及树突退化，尽管皮质持续退化。
这些发现揭示了 CRTC1 在联想记忆过程中海马中的关键作用，并提供了证据表明，CRTC1 失调是神经退行性过程中记忆缺陷的基础。
