title: p38 MAP kinase-mediated NMDA receptor-dependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer's disease.
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.
authors.affiliation: Dementia Research Unit, School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, Australia. a.ittner@unsw.edu.au.
authors.forename: Arne A
authors.initials: AA
authors.lastname: Ittner
authors.affiliation: Dementia Research Unit, School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, Australia. a.gladbach@unsw.edu.au.
authors.forename: Amadeus
authors.initials: A
authors.lastname: Gladbach
authors.affiliation: Dementia Research Unit, School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, Australia. j.bertz@unsw.edu.au.
authors.forename: Josefine
authors.initials: J
authors.lastname: Bertz
authors.affiliation: Dementia Research Unit, School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, Australia. lisa.suh@unsw.edu.au.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Suh
authors.affiliation: Dementia Research Unit, School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, Australia. l.ittner@unsw.edu.au.|Neuroscience Research Australia (NeuRA), Sydney, Australia. l.ittner@unsw.edu.au.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ittner
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D065818:Gamma Rhythm; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011725:Pyridines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D019782:Riluzole / Q000494:pharmacology; D013826:Theta Rhythm; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D019782:Riluzole; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580