P3‐042: Altered zinc neuromodulation induces neuronal hyperactivity and cognitive impairment

Abstract

Altered zinc homeostasis is implicated in the pathology of Alzheimer's disease (AD) through observations that Aβ oligomers (AβO) bind and sequester synaptic zinc, leading to synaptic deficits, and that drugs targeting zinc decrease amyloid beta (Aβ) load and improve cognition in transgenic mouse models of AD. Recently we found age-dependent increases in markers of seizure activity in the hippocampus of a transgenic mouse lacking synaptic zinc (ZnT3KO) that displays age-dependent cognitive deficits. These finding led to our hypothesis that seizure activity resulting from lack of zinc neuromodulation may contribute to development of impaired cognition. We investigated whether levetiracetam, an antiseizure drug in wide clinical use that has been shown to improve cognition in amnestic MCI patients and prevents cognitive impairment in mouse models of AD, would prevent cognitive impairment in ZnT3KO. To determine if suppression of seizure activity during a memory task can rescue the impaired cognition seen in 6 month-old ZnT3KO, we used an acute treatment administering levetiracetam 3.5 hr before training and testing in a hippocampal-dependent object location memory task (OLM). We also tested a chronic 70-day course of treatment by delivering levetiracetam using implanted osmotic pumps before assessing performance of ZnT3KO in the OLM task at 6 months of age. While 6 month ZnT3KO performed slightly above chance levels in the OLM task after acute treatment with levetiracetam, their performance was not significantly improved compared to untreated ZnT3KO mice. Conversely, chronic treatment with levetiracetam markedly improved cognition, with 6 month ZnT3KO performing equivalent to age-matched wild type mice in the OLM task. Prevention of cognitive impairment by chronic treatment with an anti-seizure drug suggests that seizure activity in ZnT3KO mice contributes to neurodegeneration and to cognitive impairment. Though acute treatment to suppress seizure activity during a memory task did not rescue cognition in 6 month ZnT3KO, the slight improvement in performance suggests that treatment at 3 months, when cognition begins to decline, may improve cognition. These results support further investigation of therapies directed to restore zinc homeostasis and normalize excitatory neurotransmission to manage neuronal hyperactivity and associated neurodegenerative changes in AD.