Abstract
Cortical and hippocampal hypersynchrony of neuronal networks seems to be an early event in Alzheimer’s disease pathogenesis. Many mouse models of the disease also present neuronal network hypersynchrony, as evidenced by higher susceptibility to pharmacologically-induced seizures, electroencephalographic seizures accompanied by spontaneous interictal spikes and expression of markers of chronic seizures such as neuropeptide Y ectopic expression in mossy fibers. This network hypersynchrony is thought to contribute to memory deficits, but whether it precedes the onset of memory deficits or not in mouse models remains unknown. The earliest memory impairments in the Tg2576 mouse model of Alzheimer’s disease have been observed at 3 months of age. We thus assessed network hypersynchrony in Tg2576 and non-transgenic male mice at 1.5, 3 and 6 months of age. As soon as 1.5 months of age, Tg2576 mice presented higher seizure susceptibility to systemic injection of a GABAA receptor antagonist. They also displayed spontaneous interictal spikes on EEG recordings. Some Tg2576 mice presented hippocampal ectopic expression of neuropeptide Y which incidence seems to increase with age among the Tg2576 population. Our data reveal that network hypersynchrony appears very early in Tg2576 mice, before any demonstrated memory impairments.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by several cognitive and behavioral troubles attacking memory functions
Spike frequency was significantly influenced by the genotype but not by the age of the animals (Fig. 2B, two-way ANOVA; transgene effect: p = 0.013; age effect: p = 0.4091; interaction: p = 0.3865). These results clearly show that spontaneous epileptiform activity is already present in Tg2576 mice as early as 1.5 months of age
To assess the occurrence of chronic seizures in Tg2576 mice, we looked for neuropeptide Y (NPY) ectopic expression in mossy fibers of the dentate gyrus by using NPY immunohistochemistry (Fig. 3)
Summary
All experiments were performed in strict accordance with the policies of the European Union (86/609/EEC), the French National Committee of Ethics (87/848), and the local committee's recommendations (C 31–555–11, Direction départementale de la protection des populations) for the care and use of laboratory animals. Animal facility of the CRCA is fully accredited by the French Direction of Veterinary Services (C 31–555–11, Feb 9, 2011) and animal surgery and experimentation conducted in this study were authorized by the French Direction of Veterinary Services (#31–11555521, 2002). All efforts were made to improve animals’ welfare and minimize animals’ suffering.
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