Project Summary/Abstract Alzheimer's disease (AD) is a form of dementia characterized by memory loss and progressive cognitive impairments. The leading hypotheses over the past decade have assumed that these symptoms are due to accumulation of amyloid-beta (Aβ) and tau proteins that lead to neurodegeneration. However, treatments that reduce Aβ levels have largely been ineffective in clinical trials and strategies to target tau have proven difficult. Numerous failed drug trials have raised concerns that reducing pathological proteins without preventing or reversing functional changes in the affected cells and networks may be insufficient for treatment. This highlights a need to examine how AD pathology impacts brain regions, connections, and activity patterns that are important for memory. By investigating specific circuits that are known to be vulnerable early in disease progression, we can gain valuable insight into the initial network changes underlying progressive cognitive decline and identify possible targets for early therapeutic interventions. Given the strong evidence for dysfunction in hippocampal processing and spatial memory in AD, it is critical to understand whether these changes are driven by abnormal inputs or local hippocampal changes. The medial entorhinal cortex (MEC) provides critical spatial inputs to the hippocampus and its vulnerability in early AD is well established. Therefore, this proposal will test the hypothesis that changes in MEC function emerge prior to cognitive decline and hippocampal processing deficits, and provide an early point of circuit dysfunction that could drive development of memory impairments. In Aim 1, we will first use in vitro electrophysiology to characterize how intrinsic properties of distinct cell types in MEC and CA1 are altered during the progression of memory impairments. In Aim 2, we will use silicon probes to simultaneously record from 512 channels throughout MEC and hippocampus to determine how and when synchrony of single units and local field potentials (LFPs) within and across regions breaks down in models of AD pathology. In Aim 3, we will use in vivo calcium imaging with miniature microscopes to track the development of spatial coding deficits across months in MECII, MECIII, and CA1 neurons as mice run on a linear track and explore an open field. Specialized viral targeting tools will allow us to isolate specific MEC subpopulations and test the hypothesis that MECII stellate cells exhibit altered spatial coding prior to deficits in CA1. These experiments will use 3 distinct mouse models of AD pathology and neurodegeneration covering Aβ (APP-KI), tau (P301S), and combinatorial (3x-Tg) transgenes to identify convergent mechanisms of circuit dysfunction across models. Together, these aims will isolate specific circuits that break down to produce memory deficits in mouse models of AD pathology.