Gender-Specific Hippocampal Dysrhythmia and Aberrant Hippocampal and Cortical Excitability in the APPswePS1dE9 Model of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a multifactorial disorder leading to progressive memory loss and eventually death. In this study an APPswePS1dE9 AD mouse model has been analyzed using implantable video-EEG radiotelemetry to perform long-term EEG recordings from the primary motor cortex M1 and the hippocampal CA1 region in both genders. Besides motor activity, EEG recordings were analyzed for electroencephalographic seizure activity and frequency characteristics using a Fast Fourier Transformation (FFT) based approach. Automatic seizure detection revealed severe electroencephalographic seizure activity in both M1 and CA1 deflection in APPswePS1dE9 mice with gender-specific characteristics. Frequency analysis of both surface and deep EEG recordings elicited complex age, gender, and activity dependent alterations in the theta and gamma range. Females displayed an antithetic decrease in theta (θ) and increase in gamma (γ) power at 18-19 weeks of age whereas related changes in males occurred earlier at 14 weeks of age. In females, theta (θ) and gamma (γ) power alterations predominated in the inactive state suggesting a reduction in atropine-sensitive type II theta in APPswePS1dE9 animals. Gender-specific central dysrhythmia and network alterations in APPswePS1dE9 point to a functional role in behavioral and cognitive deficits and might serve as early biomarkers for AD in the future.

Motor Cortex Theta and Gamma Architecture in Young Adult APPswePS1dE9 Alzheimer Mice

“…Male APPswePS1dE9 mice exhibited significant increase in relative activity in the light, dark and total circadian rhythm at the age of 18 wks. No further alterations were detected [31]. Importantly, in contrast to the complex alterations in hippocampal theta which we reported previously, no significant alterations were detected in motor cortex (M1) theta activity in APPswePS1dE9.…”

“…We further analyzed the influence of the activity stage. Note that no differences in relative activity could be detected for any of the ages and circadian cycles studied in APPswePS1dE9 mice and controls [31]. Male APPswePS1dE9 mice exhibited significant increase in relative activity in the light, dark and total circadian rhythm at the age of 18 wks.…”

“…We have previously reported that male APPswePS1dE9 exhibit a reduction in hippocampal theta at an age of 14 wks that vanished while animals are getting older [31]. In contrast, females exhibited a hippocampal theta power reduction at later stage of 18 and 19 wks of age.…”

“…Recent investigations [21, 30] focused on the analysis of early Alzheimer’s disease stages (animals aged 2.5–4.5 months) as this critical time range marks the first appearance of amyloid plaques. Lately, we performed a long-term radiotelemetric study of hippocampal frequency characteristics in young adult (14–19 wks old) APPswePS1dE9 mice using a Fast Fourier Transformation (FFT) based approach [31]. Automatic seizure detection unraveled severe gender-specific electroencephalographic seizure activity in both M1 and CA1 deflection.…”

“…Seizure activity in APPswePS1dE9 exhibited high variability as has been reported for other AD mouse models before. Importantly, hippocampal EEG frequency analysis elicited complex age, gender and activity dependent alterations in the theta and gamma range [31]. Females displayed an antithetic decrease in theta (θ) and increase in gamma (γ) power at 18–19 weeks of age whereas related changes in males appeared earlier at 14 weeks of age.…”