Abstract
Hypersynchronicity of neuronal brain circuits is a feature of Alzheimer’s disease (AD). Mouse models of AD expressing mutated forms of the amyloid-β precursor protein (APP), a central protein involved in AD pathology, show cortical hypersynchronicity. We studied hippocampal circuitry in APP23 transgenic mice using telemetric electroencephalography (EEG), at the age of onset of memory deficits. APP23 mice display spontaneous hypersynchronicity in the hippocampus including epileptiform spike trains. Furthermore, spectral contributions of hippocampal theta and gamma oscillations are compromised in APP23 mice, compared to non-transgenic controls. Using cross-frequency coupling analysis, we show that hippocampal gamma amplitude modulation by theta phase is markedly impaired in APP23 mice. Hippocampal hypersynchronicity and waveforms are differentially modulated by injection of riluzole and the non-competitive N-methyl-D-aspartate (NMDA) receptor inhibitor MK801, suggesting specific involvement of voltage-gated sodium channels and NMDA receptors in hypersynchronicity thresholds in APP23 mice. Furthermore, APP23 mice show marked activation of p38 mitogen-activated protein (MAP) kinase in hippocampus, and injection of MK801 but not riluzole reduces activation of p38 in the hippocampus. A p38 inhibitor induces hypersynchronicity in APP23 mice to a similar extent as MK801, thus supporting suppression of hypersynchronicity involves NMDA receptors-mediated p38 activity. In summary, we characterize components of hippocampal hypersynchronicity, waveform patterns and cross-frequency coupling in the APP23 mouse model by pharmacological modulation, furthering the understanding of epileptiform brain activity in AD.
Highlights
Alzheimer’s disease (AD) is characterized by cognitive decline, and presents histopathologically with amyloid-β (Aβ) deposition in extracellular plaques and intracellular neurofibrillary tangles made up of hyperphosphorylated tau [1,2]
We examined hippocampal hypersynchronicity in adult APP23 transgenic mice using in vivo telemetric electroencephalography (EEG) in free-roaming mice and analyse interictal recording sequences for spectral amplitude distribution and cross-frequency coupling (CFC) strength before the onset of plaque pathology
We show that APP23 mice have marked alterations in theta and gamma oscillations and impaired cross-frequency gamma modulation by the phase of theta oscillations
Summary
Alzheimer’s disease (AD) is characterized by cognitive decline, and presents histopathologically with amyloid-β (Aβ) deposition in extracellular plaques and intracellular neurofibrillary tangles made up of hyperphosphorylated tau [1,2]. Besides these pathological hallmarks, it is becoming increasingly clear that AD is associated with alterations in neuronal circuit excitability. Two main oscillations reflect physiological synchronous activities, both being implicated in behavioural states and memory performance: theta oscillations (4-12 Hz), generated by synchronous phasic firing of pyramidal cells [11,12], and gamma oscillations (25-100 Hz), generated by circuits between GABAergic interneurons and pyramidal cells [13]. Aberrant generation of electroencephalographic oscillations has been observed in cognitive impairment and AD [21], and aberrant hippocampal oscillations have been suggested to occur early in development of AD [22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
