UC Irvine

While it has been known for a while that patients with Alzheimer’s Disease (AD) have increased risk of unprovoked seizures, only recently has hyperexcitability become a major focus of AD research. Increased hippocampal activity in patients with mild cognitive impairment (MCI) was initially thought to be a beneficial compensatory mechanism; however, recent research has shown that patients with MCI treated with antiepileptic drugs have improved cognition. Synaptic zinc, co-released with amyloid-β (Aβ) during neurotransmission, is implicated in both oligomer formation and modulation of excitatory neurotransmission. Synaptic zinc is packaged into vesicles by ZnT3; thus, ZnT3-/- mice lack synaptically-released zinc. These mice exhibit increased seizure susceptibility, synaptic dysfunction, and age-dependent increases in markers of seizure activity, synaptic loss, and neurodegeneration, strikingly similar to AD mouse models. Although ZnT3-/- mice do not exhibit spontaneous convulsive seizures, our data suggest that these mice exhibit epileptiform activity. In addition, our data demonstrate that chronic, but not acute, treatment with the antiepileptic drug Levetiracetam (LEV) prevents age-related cognitive decline in these mice, suggesting a mechanism of action independent of antiseizure activity. In this regard, the mechanism by which LEV prevents cognitive decline is not understood.

The goal of this project was to begin characterizing the mechanism of action of LEV leading to the prevention of cognitive decline in aged ZnT3-/- mice. mRNA was extracted from 6-month-old ZnT3-/- and wildtype (WT) sex-matched mice and analyzed using NanoString. Gene analysis indicated sex-specific changes genes involved in epigenetics, neurogenesis, and hyperexcitability following LEV treatment. To investigate the effects of chronic LEV on neurogenesis important for learning and memory, ZnT3-/- mice were fed bromodeoxyuridine and immunohistochemistry was performed on brain sections. Although there was an increase in neurogenesis in LEV-treated animals, this increase was restricted to females, further suggesting a sex-specific effect of LEV. Lastly, ZnT3-/- mice were implanted with surface electroencephalogram (EEG) electrodes and the results suggest abnormal EEG activity in aged ZnT3-/- mice. Taken together, these results suggest that LEV prevents cognitive impairment in ZnT3-/- mice in a sex-specific manner at multiple layers of regulation, including epigenetics, neurogenesis, and hyperexcitability.