Department of Neuroscience, Baylor College of Medicine, USA.
Department of Physiology, Michigan State University, USA.
Prog Neurobiol. 2024 Jun;237:102612. doi: 10.1016/j.pneurobio.2024.102612. Epub 2024 Apr 19.
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.
反复发作的癫痫会导致海马齿状回颗粒细胞中活性依赖性转录因子 ∆FosB 的积累，这种现象不仅存在于癫痫的动物模型中，也存在于阿尔茨海默病（AD）的动物模型中，而且与癫痫发作频率的增加有关。在 AD 患者和相关的动物模型中，∆FosB 的积累程度与认知缺陷的严重程度成正比。我们之前发现，∆FosB 通过表观遗传调控参与突触可塑性的靶基因（如钙结合蛋白）的表达，从而损害小鼠的空间记忆。然而，在神经元过度兴奋的情况下抑制钙结合蛋白已被证明可以为齿状回颗粒细胞提供神经保护，这表明 ∆FosB 可能在较长时间内协调神经保护途径。为了验证这一假设，我们在表达突变型人淀粉样前体蛋白（APP）的转基因小鼠中，通过病毒介导的 ∆JunD 表达来干扰 ∆FosB 信号通路数月，这些小鼠会自发发生癫痫，并且会发展出 AD 相关的神经病理学和认知缺陷。我们的结果表明，持续的 ∆FosB 活性通过海马目标基因调控的离散模式发挥作用，调节神经元兴奋性、限制复发性癫痫活动，并为 APP 小鼠的海马齿状回颗粒细胞提供神经保护。
