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Easton Center for Alzheimer&apos;s Disease Research and Care","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,13]]},"abstract":"<jats:p>Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The \u03b3-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer\u2019s disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases \u03b3-oscillations and improves cognition\/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the \u03b3-aminobutyric acid type A receptors most likely assembled from \u03b11\u03b22\u03b4 subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of \u03b3-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive\/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brain\u2019s endogenous \u03b3-oscillations through enhancing the function of PV+INs.<\/jats:p>","DOI":"10.1073\/pnas.2400420121","type":"journal-article","created":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T13:45:07Z","timestamp":1722951907000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":10,"title":["A therapeutic small molecule enhances \u03b3-oscillations and improves cognition\/memory in Alzheimer\u2019s disease model mice"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1173-4734","authenticated-orcid":false,"given":"Xiaofei","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Neurology, The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095"},{"name":"Department of Neurosurgery, The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus J.","family":"Campagna","sequence":"additional","affiliation":[{"name":"Department of Neurology, Drug Development Laboratory, Mary S. 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