Tinston Jennifer, Hudson Matthew R, Harutyunyan Anna, Chen Zhibin, Jones Nigel C
Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia.
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.
Epilepsia. 2025 Mar;66(3):886-898. doi: 10.1111/epi.18222. Epub 2024 Dec 30.
The 5xFAD mouse model of Alzheimer disease (AD) recapitulates amyloid-beta (Aβ) deposition and pronounced seizure susceptibility observed in patients with AD. Forty-hertz audiovisual stimulation is a noninvasive technique that entrains gamma neural oscillations and can reduce Aβ pathology and modulate glial expression in AD models. We hypothesized that 40-Hz sensory stimulation would improve seizure susceptibility in 5xFAD mice and this would be associated with reduction of plaques and modulation of glial phenotypes.
5xFAD mice and wild-type (WT) littermates received 1 h/day 40-Hz audiovisual stimulation or sham (n = 7-11/group), beginning 2 weeks before and continuing throughout amygdala kindling epileptogenesis. Postmortem analyses included Aβ pathology and morphology of astrocytes and microglia.
5xFAD mice exhibited enhanced susceptibility to seizures compared to WT, evidenced by fewer stimulations to reach kindling endpoint (incidence rate ratio [IRR] = 1.46, p < .0001) and a trend to higher seizure severity (odds ratio [OR] = .34, p = .059). Forty-hertz stimulation reduced the behavioral severity of the first seizure (OR = 4.04, p = .02) and delayed epileptogenesis, increasing the number of stimulations required to reach kindling endpoint (IRR = .82, p = .01) compared to sham, regardless of genotype. 5xFAD mice receiving sensory stimulation exhibited ~50% reduction in amyloid pathology compared to sham. Furthermore, markers of astrocytes and microglia were upregulated in both genotypes receiving 40-Hz stimulation.
Forty-hertz sensory entrainment slows epileptogenesis in the mouse amygdala kindling model. Although this intervention improves Aβ pathology in 5xFAD mice, the observed antiepileptogenic effect may also relate to effects on glia, because mice without Aβ plaques (i.e., WT) also experienced antiepileptogenic effects of the intervention.
阿尔茨海默病（AD）的5xFAD小鼠模型再现了AD患者中观察到的淀粉样β蛋白（Aβ）沉积和明显的癫痫易感性。40赫兹视听刺激是一种非侵入性技术，可诱导γ神经振荡，并能减少AD模型中的Aβ病理变化并调节胶质细胞表达。我们假设40赫兹感觉刺激会改善5xFAD小鼠的癫痫易感性，且这将与斑块减少和胶质细胞表型调节相关。
5xFAD小鼠和野生型（WT）同窝小鼠从杏仁核点燃癫痫发生前2周开始，每天接受1小时的40赫兹视听刺激或假刺激（每组n = 7 - 11只），并持续至整个过程。死后分析包括Aβ病理以及星形胶质细胞和小胶质细胞的形态。
与WT相比，5xFAD小鼠对癫痫发作的易感性增强，表现为达到点燃终点所需的刺激次数更少（发病率比[IRR] = 1.46，p <.0001），且癫痫发作严重程度有升高趋势（优势比[OR] =.34，p =.059）。与假刺激相比，无论基因型如何，40赫兹刺激均降低了首次癫痫发作的行为严重程度（OR = 4.04，p =.02）并延迟了癫痫发生，增加了达到点燃终点所需的刺激次数（IRR =.82，p =.01）。接受感觉刺激的5xFAD小鼠与假刺激相比，淀粉样病理变化减少了约50%。此外，在接受40赫兹刺激的两种基因型中，星形胶质细胞和小胶质细胞的标志物均上调。
40赫兹感觉诱导可减缓小鼠杏仁核点燃模型中的癫痫发生。尽管这种干预改善了5xFAD小鼠的Aβ病理变化，但观察到的抗癫痫发生作用也可能与对胶质细胞的影响有关，因为没有Aβ斑块的小鼠（即WT）也经历了该干预的抗癫痫发生作用。
