Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

Abstract

Maternal choline supplementation (MCS) improves cognition in Alzheimer’s disease (AD) models. However, effects of MCS on neuronal hyperexcitability in AD are unknown. We investigated effects of MCS in a well-established mouse model of AD with hyperexcitability, the Tg2576 mouse. The most common type of hyperexcitability in Tg2576 mice, and many other mouse models and AD patients, are generalized EEG spikes (interictal spikes; IIS). Hyperexcitability is also reflected by elevated expression of the transcription factor ΔFosB in the granule cells (GCs) of the dentate gyrus (DG), which are the principal cell type. We also studied the hilus of the DG because hilar neurons regulate GC excitability. We found reduced expression of the neuronal marker NeuN within hilar neurons in Tg2576 mice, which other studies have shown is a sign of oxidative stress or other pathology.Tg2576 breeding pairs received a diet with a relatively low, intermediate or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC ΔFosB expression was reduced, and NeuN expression was restored. Spatial memory improved using the novel object location task. In contrast, offspring exposed to the relatively low choline diet had several adverse effects, such as increased mortality. They had the weakest hilar NeuN immunoreactivity and greatest GC ΔFosB. However, their IIS frequency was low, which was surprising. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have mixed effects. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, ΔFosB and spatial memory in an animal model of AD.