Institut de Neurociències, Department de Bioquímica i Biologia Molecular, Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Barcelona, Spain.
Institut de Neurociències, Department de Bioquímica i Biologia Molecular, Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Barcelona, Spain.
Biol Psychiatry. 2019 Jul 15;86(2):87-96. doi: 10.1016/j.biopsych.2019.01.006. Epub 2019 Jan 17.
Synapse-to-nucleus signaling is critical for converting signals received at synapses into transcriptional programs essential for cognition, memory, and emotion. This neuronal mechanism usually involves activity-dependent translocation of synaptonuclear factors from synapses to the nucleus resulting in regulation of transcriptional programs underlying synaptic plasticity. Acting as synapse-to-nucleus messengers, amyloid precursor protein intracellular domain associated-1 protein, cAMP response element binding protein (CREB)-regulated transcription coactivator-1, Jacob, nuclear factor kappa-light-chain-enhancer of activated B cells, RING finger protein 10, and SH3 and multiple ankyrin repeat domains 3 play essential roles in synapse remodeling and plasticity, which are considered the cellular basis of memory. Other synaptic proteins, such as extracellular signal-regulated kinase, calcium/calmodulin-dependent protein kinase II gamma, and CREB2, translocate from dendrites or cytosol to the nucleus upon synaptic activity, suggesting that they could contribute to synapse-to-nucleus signaling. Notably, some synaptonuclear factors converge on the transcription factor CREB, indicating that CREB signaling is a key hub mediating integration of synaptic signals into transcriptional programs required for neuronal function and plasticity. Although major efforts have been focused on identification and regulatory mechanisms of synaptonuclear factors, the relevance of synapse-to-nucleus communication in brain physiology and pathology is still unclear. Recent evidence, however, indicates that synaptonuclear factors are implicated in neuropsychiatric, neurodevelopmental, and neurodegenerative disorders, suggesting that uncoupling synaptic activity from nuclear signaling may prompt synapse pathology, contributing to a broad spectrum of brain disorders. This review summarizes current knowledge of synapse-to-nucleus signaling in neuron survival, synaptic function and plasticity, and memory. Finally, we discuss how altered synapse-to-nucleus signaling may lead to memory and emotional disturbances, which is relevant for clinical and therapeutic strategies in neurodegenerative and neuropsychiatric diseases.
突触核信号对于将突触接收的信号转换为认知、记忆和情绪所必需的转录程序至关重要。这种神经元机制通常涉及突触核因子从突触到核的活性依赖性易位，导致调节突触可塑性的转录程序。作为突触核信使，淀粉样前体蛋白细胞内域相关蛋白 1、cAMP 反应元件结合蛋白（CREB）调节转录共激活因子 1、Jacob、核因子 kappa-轻链增强子的激活 B 细胞、RING 指蛋白 10 和 SH3 和多个锚蛋白重复结构域 3 在突触重塑和可塑性中发挥重要作用，这被认为是记忆的细胞基础。其他突触蛋白，如细胞外信号调节激酶、钙/钙调蛋白依赖性蛋白激酶 II 伽马和 CREB2，在突触活动时从树突或细胞质易位到核内，表明它们可能有助于突触核信号。值得注意的是，一些突触核因子集中在转录因子 CREB 上，表明 CREB 信号是整合突触信号到神经元功能和可塑性所需的转录程序的关键枢纽。尽管已经做出了很大的努力来确定突触核因子的鉴定和调节机制，但突触核通讯在大脑生理学和病理学中的相关性仍不清楚。然而，最近的证据表明，突触核因子与神经精神、神经发育和神经退行性疾病有关，这表明将突触活动与核信号解耦可能会促使突触病理学，导致广泛的脑疾病。本综述总结了目前关于神经元存活、突触功能和可塑性以及记忆中的突触核信号的知识。最后，我们讨论了突触核信号的改变如何导致记忆和情绪障碍，这与神经退行性和神经精神疾病的临床和治疗策略有关。
