Project Summary/Abstract Alzheimer's disease (AD) is a form of dementia characterized by memory loss and progressive cognitive impairments. Memory impairments in AD increase with age and are linked to hyperexcitability, interneuron death, circuit remodeling, and impaired interneuron function. Interneuron loss and dysfunction are well established in AD, yet it remains unclear how these anatomical changes contribute to cognitive deficits. Interneurons play a critical role in synchronizing local networks to generate brain rhythms important for long- term potentiation and memory encoding and interneuron loss has been associated with reduced oscillations and memory impairments in AD models. Understanding how hippocampal interneurons are functionally altered in AD, both before and after the emergence of learning impairments, is critical to understanding these cognitive deficits. In this proposal, we will test the hypothesis that hippocampal interneuron synchrony is altered in AD model mice, and that network dysfunction in young, pre-symptomatic mice can predict memory impairments. To examine the relationship between interneuron activity and local networks, we will use silicon probes to record simultaneously from local field potentials and single units throughout CA1 and dentate gyrus (DG) of 3xTg-AD and wild type mice running in virtual reality. We will first examine the firing patterns of interneurons in 6 month old AD model mice, after the onset of memory impairments. We hypothesize that interneurons in AD model mice will have abnormal firing patterns relative to network oscillations, which will desynchronize interneurons across CA1 and DG. Next, we will use young 3xTg-AD mice, prior to memory impairments, in order to investigate whether specific network changes can predict future cognitive decline. We hypothesize that alterations in network function (such as interneuron phase locking, oscillation power or coherence) will predict the severity of memory impairments at a later time point. These experiments will highlight potential targets for early therapeutic interventions and lead to new insights into the progression of memory impairments in AD. Characterizing hippocampal desynchrony in AD and how it contributes to cognitive deficits will be critical in developing targeted treatments for AD, especially preventative intervention during the pre-symptomatic phase where success is most viable.