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The NMDA receptor subunit GluN3A regulates a program of synaptic activity-induced and MEF2C-dependent transcription

ABSTRACT: N-methyl-D-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the GluN2 subunit composition of NMDARs determines whether NMDARs activate the transcription factor CREB. However, whether the developmentally-regulated GluN3A subunit also modulates NMDAR-induced transcription was unknown. Here we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. This enhancement is mediated by the accumulation of phosphorylated p38 MAP kinase in the nucleus, which drives the activation of the transcription factor MEF2C and promotes the transcription of a subset of synaptic activity-induced genes including Bdnf and Arc. Our evidence that GluN3A negatively regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity on the program of synaptic activity-regulated gene transcription in developing neurons.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE133917 | GEO | 2019/07/08

REPOSITORIES: GEO

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Project description:INTRODUCTION Alzheimer’s disease (AD) is an advanced neurodegenerative disorder characterized by progressive impairment in both memory loss and cognitive capacities, which resulting in severe dementia [1]. The pathogenesis of AD is complicated and poorly understood. According to the World Alzheimer Report 2018, it is estimated that AD affects at least 50 million persons throughout the world, and the number of people with AD will double nearly every 20 years [2]. Over the past decade, various theories have been developed for the neuropathological level of AD, but the most popular distinct pathological hallmarks is extracellular accumulation of amyloid beta (Aβ) plaques, as well as the neurofibrillary tangles (NFTs) composed of the hyperphosphorylated tau in the form of in the select brain regions [3]. The other factors including mitochondrial dysfunction, oxidative stress, brain inflammation and neurotransmitter disturbances pathology have been recognized as a contributing factor in the pathogenesis of AD [4]. To date, only symptomatic therapies are available for AD patients. Cholinesterase inhibitors (CIs) are approved for mild to moderate AD patients, and memantine is the only one N-methyl-D-aspartate receptor (NMDAR) antagonist has been approved for moderate to severe AD [5]. NMDAR is a glutamate ionotropic receptor, they display high Ca2+ permeability and voltage-dependent block by Mg2+[6]. In AD patients, NMDARs could be overactivated due to increasing glutamate release from presynaptic neurons. Overactived NMDARs lead first to Ca2+ overload in postsynaptic neurons, followed by desensitization and internalization, resulting in synaptic dysfunction and ultimately cell death [7, 8]. The numerous factors than can influence the levels of endogenous glutamate release in the pathogenesis of AD, deposition of Aβplaques, soluble Aβoligomers, NFTs, mitochondrial dysfunction and oxidative stress have been associated with the higher concentration of glutamate release[9, 10]. Memantine is an uncompetitive, moderate affinity NMDA receptor (NMDAR) antagonist which is used for a further therapeutic option of moderate to severe AD [5]. Its effects have been investigated in a large number of in vitro and in vivo studies, which indicated that memantine can against Aβ-induced glutamate-mediated toxicity, attenuate phosphorylation of tau and reduces level of total precursor protein (APP) in human neuroblastoma SK-N-SH cells [11], and lower Aβ1-42 secretion and plaques in primary cortical neuronal culture cells [9, 12]. Some studies showed that memantine also completely protected against Aβ-induced ROS injure in the primary hippocampal neurons [13]. Studies with transgenic animal models showed that memantine reduced the levels of soluble Aβ1-42, Aβ plaque deposition and lowered the loss of synaptic density in APP/PS1mice [4, 14, 15], and decreased the levels of total tau and hyperphosphorylated tau in 3×Tg-AD mice [3]. Furthermore, memantine altered genes expression in adult rat brain [16], and modulated protein profiles in Down syndrome mice brain [17]. However, no comprehensive study of proteomic characteristics description of 3×Tg-AD transgenic mice under the memantine treatment has been conducted to date as far as we searched. In order to better understand the multiple actions of memantine, we conducted detailed analysis of proteomics and bioinformatics to dissect the molecular mechanisms of memantine for the treatment of AD.

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The NMDA receptor subunit GluN3A regulates a program of synaptic activity-induced and MEF2C-dependent transcription

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