# Subcortical Nodes Within Epileptic Network Control the Cortical Disfacilitation to Prompt Seizure Onset in IGE Mouse Model > **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $237,878 ## Abstract Alzheimer’s disease affects more than 5.5 million people of all ages in US and 200,000 peoples younger than 65 also develop early Alzheimer symptoms, creating tremendous burdens for patients, their families and communities. These patients show chronic/progressive memory dysfunction and dementia at late old ages. Until now all clinical trials for Alzheimer‘s disease treatment have failed. Regardless of many animal models with genetic manipulations to exhibit chronic pathogenesis of this disease, it remains unknown how Alzheimer’s disease memory dysfunction/dementia symptoms(both familial and sporadic) evolve from normal brain state at early young ages to pathological memory dysfunction/neurodegeneration state at late old ages. Along this whole transitioning course, Alzheimer patients’ sleep patterns have dramatically reduced slow-wave sleep(SWS) duration and relatively increased rapid eye-movement(REM) sleep, which will likely elevate cortical/hippocampal neuron excitability and play determined roles in Alzheimer’s disease pathogenesis. Compatible with this idea, preclinical silent epileptic activity in hippocampus has been recorded from sleeping Alzheimer patients[1] and sleep deprivation can dramatically increase amyloid-β peptides[2]/APOE ɛ4 level in brain[3, 4]. In addition, amyloid-β peptides are already present in different cortex areas before memory dysfunction and dementia manifest/are noticeable[5]. Thus, this proposal will apply one finding (sleep-like slow- wave oscillations(SWOs) induced state-dependent homeostatic synaptic potentiation) from my current R01 work to study pathophysiological mechanism at early stage of Alzheimer’s disease, using a 5XFAD mouse model and human amyloid-β peptide extracts. Specifically, we hypothesize that sleep-like cortical neuron up- state activity during sleep can cause state-dependent synaptic potentiation in hippocampal CA1 pyramidal neurons from both wide-type and 5XFAD Alzheimer’s model at young ages. Moreover, more up-state activity coming from cortical neurons during REM sleep in 5XFAD mice can chronically/progressively saturate excitatory synaptic strength of hippocampal CA1 pyramidal neurons before synaptic disruption along the ageing course. Consequentially, these saturated synaptic events can ferociously drive up generation of high level amyloid-β peptides in 5XFAD mice, which can suppress this state-dependent excitatory synaptic saturation in hippocampal CA1 pyramidal neurons and lead to synaptic attenuation and disruption. Thus, it is the chronic increased neuronal hyperexcitability/saturated excitatory synaptic activity in pyramidal neurons during altered SWS/REM sleep in 5XFAD mice that viciously drive up amyloid-β peptide generation. Eventually, these high-level amyloid-β peptides form insoluble fibrillar plaques(with tau protein neurofibrillary tangles to involve subsequently[5]), transitioning to early stage of Alzheimer’s disease with neurodegeneration at late old ages. This will offer ... ## Key facts - **NIH application ID:** 10124942 - **Project number:** 3R01NS107424-03S1 - **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER - **Principal Investigator:** Chengwen Zhou - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $237,878 - **Award type:** 3 - **Project period:** 2018-08-15 → 2023-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10124942 ## Citation > US National Institutes of Health, RePORTER application 10124942, Subcortical Nodes Within Epileptic Network Control the Cortical Disfacilitation to Prompt Seizure Onset in IGE Mouse Model (3R01NS107424-03S1). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10124942. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*