Browsing by Author "Tomchik, Seth M."

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    Dopamine, sleep, and neuronal excitability modulate amyloid-?-mediated forgetting in Drosophila
    (Public Library of Science, 2021-10-07T00:00:00) Kaldun, Jenifer C.; Lone, Shahnaz R.; Humbert Camps, Ana M.; Fritsch, Cornelia; Widmer, Yves F.; Stein, Jens V.; Tomchik, Seth M.; Sprecher, Simon G.
    Alzheimer disease (AD) is one of the main causes of age -related dementia and neurodegeneration. However, the onset of the disease and the mechanisms causing cognitive defects are not well understood. Aggregation of amyloidogenic peptides is a pathological hallmark of AD and is assumed to be a central component of the molecular disease pathways. Panneuronal expression of A?42 Arctic peptides in Drosophila melanogaster results in learning and memory defects. Surprisingly, targeted expression to the mushroom bodies, a center for olfactory memories in the fly brain, does not interfere with learning but accelerates forgetting. We show here that reducing neuronal excitability either by feeding Levetiracetam or silencing of neurons in the involved circuitry ameliorates the phenotype. Furthermore, inhibition of the Rac-regulated forgetting pathway could rescue the A?42 Arctic-mediated accelerated forgetting phenotype. Similar effects are achieved by increasing sleep, a critical regulator of neuronal homeostasis. Our results provide a functional framework connecting forgetting signaling and sleep, which are critical for regulating neuronal excitability and homeostasis and are therefore a promising mechanism to modulate forgetting caused by toxic A? peptides. � 2021 Kaldun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.