Project Summary Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive age- related cognitive decline. Abnormal brain rhythms and interneuron dysfunction have been implicated in AD, but it is unclear how these changes contribute to memory deficits. Studies linking specific network activity patterns in specific circuits to memory decline will be needed in order to leverage new neurostimulation technologies to normalize activity in these circuits and improve memory. Interneurons play a critical role in synchronizing local networks to facilitate memory, but their contribution to impaired hippocampal function in AD is not well understood. My lab has previously shown that proper timing of hippocampal interneuron firing is disrupted in a mouse model of epilepsy, leading to desynchronized communication in the hippocampal circuit. Hyperexcitability, seizures, and interneuron dysfunction have been found in animal models of both epilepsy and AD, suggesting that cognitive dysfunction in these diseases may share common mechanisms. In this proposal, I will test the hypothesis that the timing of hippocampal interneuron firing relative to local oscillations is disrupted in 3xTg-AD mice and that these changes are predictive of future memory impairments. I will use in vivo electrophysiology with silicon probes to record local field potentials and single units throughout CA1, CA3, and dentate gyrus (DG) in head-fixed 3xTg and wild type mice running in a virtual reality environment. Recordings and behavioral tests will be performed in the same animals before and after the emergence of memory impairments. I hypothesize that interneurons in AD mice will lose their temporal specificity relative to the phase of local oscillations, which will desynchronize interneurons across the hippocampus. I further expect that extent of interneuron dysfunction will predict the severity of future memory dysfunction. In order to understand what network activity patterns are associated with improved cognition in AD, I will test the hypothesis that the anti-epileptic drug Levetiracetam (LEV) improves memory by modifying hippocampal network activity and interneuron function. This drug has been shown to normalize hyperexcitability and improve memory in AD, but its precise mechanism is unknown. I will again perform silicon probe recordings in 3xTg and WT mice to measure the acute and chronic impacts of LEV on the hippocampal circuit. I hypothesize that chronic reduction of hyperexcitability by LEV will lead to improved synchrony in the hippocampus, characterized by increased coherence and theta-gamma coupling, as well as increased temporal specificity of interneuron firing. The results of these experiments will highlight specific cell populations and activity patterns associated with memory dysfunction in AD and identify potential targets for early therapeutic interventions.