PROJECT SUMMARY/ABSTRACT Brain performance declines with Alzheimer’s disease (AD) progression. The massive loss of neurons observed at advances stages of the disease are confirmatory observations of the disruption of the brain circuits governing the brain tasks affected. This is, however, too late in the progression of the disease. Beta-amyloid (Aβ) progressively accumulates over many years, surpassing its physiological levels early in the disease. Unfortunately, little is known about the effects of Aβ before the first symptoms appear. By then, it has been reported, among other things, that there is an increase in the excitability of the neurons. We found that cortical pyramidal neurons of young APPNL-G-F mice, a relatively novel mouse model of AD that does not overexpress amyloid precursor protein, but accumulates Aβ aggressively after the second month of life, present with physiological features that indicate a reduction of their intrinsic excitability when compared with neurons from age-matched controls. The same indicators 3-4 months later, when the accumulation of Aβ is significant, show a swing in their excitability, and the neurons become more excitable than in control mice, results more in agreement with the data from the literature. We believe that sustained hypoexcitability results in impaired homeostatic mechanisms of intrinsic excitability in 6-month-old mice. Our hypothesis is that early accumulation of Aβ leads to hypoexcitability of cortical neurons resulting in a pathological hyperexcitability at later stages of the disease. This abnormal switch in excitability is a consequence of an impairment of the homeostatic mechanism caused by upregulation of CaMKIV activity. The questions that arise now are how early Aβ accumulation leads to hypoexcitability, what causes the rebound in excitability a few months later, and whether there is a manipulation that could correct the hypoexcitable state to prevent the hyperexcitable state. To answer these questions we will test the following hypotheses: (1) hypoexcitability in the young APPNL-G-F mice is caused by upregulation of voltage-gated potassium channels, downregulation of voltage-gated sodium channels changes, or both, (2) defective or saturated mechanisms of homeostatic plasticity lead to hypoexcitability at younger ages, (3) homeostatic plasticity dysregulation is a direct consequence of Aβ accumulation, (4) hypoexcitability occurring during young adulthood in the progression of pathology in the APPNL-G-F mouse model is a cause of hyperexcitability at later stages (middle age), (5) early hypoexcitability results in blunted homeostatic response at middle age, due to downregulation of CaMKIV, and (6) long-term block of K+ channels using FDA- approved drugs during early stages of the pathology will increase homeostatic downregulation of excitability. We will use APP knock-in (APPNL-G-F) transgenic mice, the most clinically relevant mouse model of AD, in vivo 2PE microscopy, optogenetics, ch...