Persistent ∆FosB expression limits recurrent seizure activity and provides neuroprotection in the dentate gyrus of APP mice

持续性 ∆ fosb表达限制了反复发作的癫痫活动，并在APP小鼠的齿状回中提供了神经保护

Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer's disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection to dentate granule cells, indicating that ∆FosB may act over long timescales to coordinate neuroprotective pathways. To test this hypothesis, we used viral-mediated expression of ∆JunD to interfere with ∆FosB signaling over the course of several months in transgenic mice expressing mutant human amyloid precursor protein (APP), which exhibit spontaneous seizures and develop AD-related neuropathology and cognitive deficits. Our results demonstrate that persistent ∆FosB activity acts through discrete modes of hippocampal target gene regulation to modulate neuronal excitability, limit recurrent seizure activity, and provide neuroprotection to hippocampal dentate granule cells in APP mice.

复发性癫痫发作导致癫痫小鼠模型和阿尔茨海默氏病 (AD) 小鼠模型中海马齿状颗粒细胞中活性依赖性转录因子 ∆ fosb的积累，这也与癫痫发作的发生率增加有关。在AD患者和相关小鼠模型中，∆ fosb积累的程度与认知缺陷的严重程度增加相对应。我们先前发现 ∆ fosb通过表观遗传调节参与突触可塑性的靶基因如钙结合蛋白的表达来损害小鼠的空间记忆。然而，已证明在神经元过度兴奋的情况下抑制钙结合蛋白可对齿状颗粒细胞提供神经保护，这表明 ∆ fosb可能会在长时间内起作用以协调神经保护途径。为了检验这一假设，我们在表达突变人淀粉样前体蛋白 (APP) 的转基因小鼠中，使用 ∆ jund的病毒介导表达来干扰 ∆ fosb信号在几个月的过程中，这些小鼠表现出自发性癫痫发作并发展与AD相关的神经病理学和认知缺陷。我们的结果表明，持续性 ∆ fosb活性通过海马靶基因调控的离散模式起作用，以调节神经元兴奋性，限制复发性癫痫发作活动，并为APP小鼠的海马齿状颗粒细胞提供神经保护。

REF: Stephens GS, Park J, Eagle A, et al. Persistent ∆FosB expression limits recurrent seizure activity and provides neuroprotection in the dentate gyrus of APP mice. Prog Neurobiol. 2024;237:102612. doi:10.1016/j.pneurobio.2024.102612 PMID: 38642602

Loss of glycine receptors in the nucleus accumbens and ethanol reward in an Alzheimer´s Disease mouse model

阿尔茨海默氏病小鼠模型中伏隔核中甘氨酸受体的丢失和乙醇奖励

Alterations in cognitive and non-cognitive cerebral functions characterize Alzheimer's disease (AD). Cortical and hippocampal impairments related to extracellular accumulation of Aβ in AD animal models have been extensively investigated. However, recent reports have also implicated intracellular Aβ in limbic regions, such as the nucleus accumbens (nAc). Accumbal neurons express high levels of inhibitory glycine receptors (GlyRs) that are allosterically modulated by ethanol and have a role in controlling its intake. In the present study, we investigated how GlyRs in the 2xTg mice (AD model) affect nAc functions and ethanol intake behavior. Using transgenic and control aged-matched litter mates, we found that the GlyRα2 subunit was significantly decreased in AD mice (6-month-old). We also examined intracellular calcium dynamics using the fluorescent calcium protein reporter GCaMP in slice photometry. We also found that the calcium signal mediated by GlyRs, but not GABAAR, was also reduced in AD neurons. Additionally, ethanol potentiation was significantly decreased in accumbal neurons in the AD mice. Finally, we performed drinking in the dark (DID) experiments and found that 2xTg mice consumed less ethanol on the last day of DID, in agreement with a lower blood ethanol concentration. 2xTg mice also showed lower sucrose consumption, indicating that overall food reward was altered. In conclusion, the data support the role of GlyRs in nAc neuron excitability and a decreased glycinergic activity in the 2xTg mice that might lead to impairment in reward processing at an early stage of the disease.

认知和非认知脑功能的改变是阿尔茨海默病 (AD) 的特征。已经广泛研究了AD动物模型中与a β 细胞外积累有关的皮质和海马损伤。然而，最近的报道还涉及边缘区域 (例如伏隔核 (nAc)) 中的细胞内a β。Accumbal神经元表达高水平的抑制性甘氨酸受体 (GlyRs)，其被乙醇变构调节，并在控制其摄入中起作用。在本研究中，我们研究了2xTg小鼠 (AD模型) 中的GlyRs如何影响nAc功能和乙醇摄入行为。使用转基因和对照的年龄匹配的产仔伴侣，我们发现在AD小鼠 (6个月大) 中GlyRα2亚基显着降低。我们还在切片光度法中使用荧光钙蛋白报告基因GCaMP检查了细胞内钙动力学。我们还发现，在AD神经元中，GlyRs而不是GABAAR介导的钙信号也减少了。此外，AD小鼠的accumbal神经元中的乙醇增强作用显着降低。最后，我们进行了在黑暗中饮酒 (DID) 实验，发现2xTg小鼠在DID的最后一天消耗了较少的乙醇，这与较低的血液乙醇浓度一致。2xTg小鼠还显示出较低的蔗糖消耗，表明总体食物奖励被改变。总之，数据支持GlyRs在nAc神经元兴奋性中的作用以及2xTg小鼠中降低的甘氨酸能活性，这可能导致疾病早期的奖励处理受损。

REF: Armijo-Weingart L, San Martin L, Gallegos S, et al. Loss of glycine receptors in the nucleus accumbens and ethanol reward in an Alzheimer´s Disease mouse model. Prog Neurobiol. 2024;237:102616. doi:10.1016/j.pneurobio.2024.102616 PMID: 38723884