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

Abstract

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 β-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 bi-weekly 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 β-amyloid-plaque load, which is absent in APP/PSEN1 mice under 6 months of age.

Chronic Seizures Induce Sex-Specific Cognitive Deficits with Loss of Presenilin 2 Function

“…The CKM is a moderate-throughput, minimally invasive model routinely used in epilepsy research [38,[52][53][54][55][56]. Unlike resource-intensive video-EEG recordings of spontaneous electrographic discharges with single-housed mice with AD-associated amyloid precursor protein (APP) overexpression [31,[57][58][59][60][61][62][63], corneal kindling induces network hyperactivity in an investigator-controlled setting wherein seizure history can be clearly identified; i.e. epileptogenesis can be directly controlled to time-dependently resolve how seizures affect disease outcomes at specific times throughout life [49].…”

“…epileptogenesis can be directly controlled to time-dependently resolve how seizures affect disease outcomes at specific times throughout life [49]. Spontaneous seizures in epilepsy models are infrequent and unpredictable [64, 65], even with AD-associated mutations [63], therefore directly attributing behavioral changes to uniform seizure history is difficult, highly individualized, and requires large groups for long-duration, resource-intensive monitoring so as to have sufficient power to resolve an effect of seizures on behavior or disease modification [66, 67]. CKM can generate ample numbers of mice with uniform seizure history suited to cognitive testing [56] and pharmacological intervention [37, 41, 55].…”

“…PSEN2 KO mice are a unique platform on which to model the sequelae of chronic seizures in an AD-associated genotype [8] in the absence of accumulated Aβ. Prior studies of seizures in AD-associated rodent models have primarily relied on the pathological overexpression of APP to drive non-physiologic accumulation of Aβ [31, 59, 63]. PSEN2 KO mice are not defined by Aβ accumulation [71], this thus model provides a resource to define the Aβ-independent mechanisms underlying cognitive decline and advanced age in the setting of chronic seizures.…”