40hz Sensory Neuromodulation Is Anti-epileptogenic in a Combined Mouse Model of Epilepsy and Alzheimer's Disease
Abstract number :
3.512
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2024
Submission ID :
1586
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Jennifer Tinston, BSc (Hons) – Monash University
Matt Hudson, PhD – Monash University
Peravina Thergarajan, PhD – Monash University
Anna Harutyunyan, PhD – Walter and Eliza Hall Institute
Idrish Ali, PhD – Monash University
Presenting Author: Nigel Jones, Professor – Monash University
Rationale: The 5xFAD mouse model of Alzheimer’s disease (AD) recapitulates amyloid-beta (Aβ) deposition and pronounced seizure susceptibility which are observed in patients with AD. 40Hz audio-visual stimulation is a non-invasive technique which entrains neural oscillations and reduces Aβ pathology in AD models. We hypothesised that 40Hz sensory stimulation would improve seizure susceptibility in 5xFAD mice and this would be associated with reduction of pathogenic plaques and modulation of glial phenotypes.
Methods: In study 1, 5xFAD mice and wild-type littermates received 1hr/day 40Hz audio-visual stimulation or sham, beginning two weeks before, and continuing throughout amygdala kindling epileptogenesis. In study 2, WT mice underwent status epilepticus, followed by one-week stimulation or sham. Post-mortem analyses included Aβ pathology, morphological assessment of astrocytes and microglia, gene expression analysis and spectral EEG studies.
Results: 5xFAD mice exhibited enhanced susceptibility to seizures compared to WT, evidenced by higher seizure severity (p=0.04), and accelerated kindling (p< 0.0001). 40Hz sensory stimulation reduced the behavioral severity of the first seizure (p=0.04) and delayed epileptogenesis compared to sham (p=0.02), regardless of genotype. 5xFAD mice receiving sensory stimulation exhibited ~50% reduction in amyloid pathology, compared to sham. In study 2, 40Hz stimulation modestly reduced epileptiform spikes after SE (p=0.1), but had marked effects on spectral power, significantly increasing delta and theta power, compared to sham. Further, immunocytochemistry and gene expression markers of astrocytes and microglia were upregulated after 40Hz stimulation in both experiments.
Conclusions: 40Hz sensory entrainment slows epileptogenesis in the mouse amygdala kindling model. While this intervention improves Aβ pathology in 5xFAD mice, the observed anti-epileptogenic effect may also be related to effects on glial morphology, since mice without Aβ plaques (i.e. WT) also benefitted from this intervention. These works promote 40Hz entrainment as a potential disease-modifying therapeutic strategy for epilepsy.
Funding: The authors acknowledge funding which supported these works received by NJ from the NHMRC (APP1557353) and ARC (APP130100100).
Basic Mechanisms