Altered synaptic glutamate homeostasis contributes to cognitive decline in young APP/PSEN1 mice

Non-convulsive epileptiform activity is a common and under-studied comorbidity of Alzheimer's disease that may significantly contribute to onset of clinical symptoms independently of other neuropathological features such as beta-amyloid deposition. We used repeated treatment with low dose kainic acid (KA) to trigger subthreshold epileptiform activity in young (less than 6 months) wild-type (WT) and APP/PSEN1 mice to test the role of disruption to the glutamatergic system in epileptiform activity changes and the development of memory deficits. Short-term repeated low-dose KA (five daily treatments with 5 mg/kg, IP) impaired long-term potentiation in hippocampus of APP/PSEN1 but not WT mice. Long-term repeated low-dose KA (fourteen weeks of biweekly treatment with 7.5-10 mg/kg) led to high mortality in APP/PSEN1 mice. KA treatment also impaired memory retention in the APP/PSEN1 mice in a Morris water maze task under cognitively challenging reversal learning conditions where the platform was moved to a new location. Four weeks of bi-weekly treatment with 5 mg/kg KA also increased abnormal spike activity in APP/PSEN1 and not WT mice but did not impact sleep/wake behavioral states. These findings suggest that hyperexcitability in Alzheimer's disease may indeed be an early contributor to cognitive decline that is independent of heavy beta-amyloid-plaque load, which is absent in APP/ PSEN1 mice under 6 months of age.

Automated summary

Repeated low-dose kainic acid treatment triggered non-convulsive epileptiform activity in APP/PSEN1 mice, leading to memory impairment and hippocampal long-term potentiation deficits. The high excitability in Alzheimer's disease may contribute to cognitive decline independently of beta-amyloid-plaque load, especially in younger mice without plaques.