de Andrés Raquel, Martínez-Blanco Elena, Díez-Guerra F Javier
Laboratory Molecular Basis of Neuronal Plasticity, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Departamento de Biología Molecular, Facultad de Ciencias, Universidad Autónoma de Madrid, Nicolás Cabrera, 1, 28049, Madrid, Spain.
Mol Neurobiol. 2025 May;62(5):5609-5628. doi: 10.1007/s12035-024-04598-3. Epub 2024 Nov 25.
The coordination of neuronal wiring and activity within the central nervous system (CNS) is crucial for cognitive function, particularly in the context of aging and neurological disorders. Neurogranin (Ng), an abundant forebrain protein, modulates calmodulin (CaM) activity and deeply influences synaptic plasticity and neuronal processing. This study investigates the regulatory mechanisms of Ng expression, a critical but underexplored area for combating cognitive impairment. Utilizing both in vitro and in vivo hippocampal models, we show that Ng expression arises during late developmental stages, coinciding with the processes of synaptic maturation and neuronal circuit consolidation. We observed that Ng expression increases in neuronal networks with heightened synaptic activity and identified GluN2B-containing N-methyl-D-aspartate (NMDA) receptors as key drivers of this expression. Additionally, we discovered that nuclear-localized HDAC4 inhibits Ng expression, establishing a regulatory axis that is counteracted by NMDA receptor stimulation. Analysis of the Ng gene promoter activity revealed regulatory elements between the - 2.4 and - 0.85 Kbp region, including a binding site for RE1-Silencing Transcription factor (REST), which may mediate HDAC4's repressive effect on Ng expression. Further analysis of the promoter sequence revealed conserved binding sites for the myocyte enhancer factor-2 (MEF2) transcription factor, a target of HDAC4-mediated transcription regulation. Our findings elucidate the interplay between synaptic activity, NMDAR function, and transcriptional regulation in controlling Ng expression, offering insights into synaptic plasticity mechanisms and potential therapeutic strategies to prevent cognitive dysfunction.
中枢神经系统（CNS）内神经元布线与活动的协调对于认知功能至关重要，在衰老和神经疾病背景下尤为如此。神经颗粒素（Ng）是一种在前脑大量存在的蛋白质，可调节钙调蛋白（CaM）的活性，并深刻影响突触可塑性和神经元加工过程。本研究调查了Ng表达的调控机制，这是对抗认知障碍的一个关键但尚未充分探索的领域。利用体外和体内海马体模型，我们发现Ng表达出现在发育后期，与突触成熟和神经元回路巩固过程一致。我们观察到，在突触活动增强的神经元网络中Ng表达增加，并确定含GluN2B的N-甲基-D-天冬氨酸（NMDA）受体是这种表达的关键驱动因素。此外，我们发现核定位的组蛋白去乙酰化酶4（HDAC4）抑制Ng表达，建立了一个被NMDA受体刺激抵消的调控轴。对Ng基因启动子活性的分析揭示了-2.4至-0.85 Kbp区域之间的调控元件，包括RE1沉默转录因子（REST）的结合位点，其可能介导HDAC4对Ng表达的抑制作用。对启动子序列的进一步分析揭示了肌细胞增强因子2（MEF2）转录因子的保守结合位点，MEF2是HDAC4介导的转录调控的靶点。我们的研究结果阐明了突触活动、NMDAR功能和转录调控在控制Ng表达中的相互作用，为突触可塑性机制和预防认知功能障碍的潜在治疗策略提供了见解。
