Authors :
Presenting Author: Christos Lisgaras, PhD – NYU Langone Health
Helen Scharfman, PhD – NYU Langone Health
Rationale:
Interictal spikes (IIS) are a common type of abnormal electrical activity in animal models of Alzheimer’s disease (AD) and AD patients. We have recently shown that high-frequency oscillations (HFOs, >250Hz) are a new type of abnormal electrical activity in AD models. However, the brain regions where IIS and HFOs are robust are not known but are important because such data would suggest sites that contribute to IIS and HFO generation. Because the hippocampus and cortex exhibit altered excitability in AD models, we asked where IIS and HFOs are robust along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the medial septohippocampal cholinergic neurons selectively would reduce IIS.Methods:
We used three mouse models of AD, Tg2576 mice, presenilin 2 knockout mice, and the Ts65Dn mouse model of Down’s syndrome. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with ChAT-Cre mice, and offspring mice were injected into the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs. We recorded local field potential along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS), and rapid eye movement (REM) sleep. Results:
We detected IIS and HFOs in all transgenic mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and were primarily during REM sleep. In contrast, HFOs were localized in the DG and occurred primarily during SWS. In all three models, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS frequency during REM sleep without affecting the overall duration or number of REM sleep bouts.
Conclusions:
Maximal IIS amplitude and robust HFO occurrence in the DG of three mouse models of AD neuropathology suggest that the DG could be one of the areas that critically contribute to hyperexcitability in AD models. Selectively reducing MS cholinergic tone could be a new strategy to reduce IIS in AD.
Funding:
NIH R01 AG-055328; NIH R01 NS-106983; New York State Office of Mental Health.