Gamma frequency entrainment attenuates amyloid load and modifies microglia

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Iaccarino HF*, Singer AC*, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH (2016) Gamma frequency entrainment attenuates amyloid load and modifies microglia, Nature 540(7632):230-235. (*, co-first authors)

Changes in gamma oscillations (20–50Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer’s disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40Hz), but not other frequencies, reduces levels of amyloid-ß (Aß)1–40 and Aß 1–42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aß. Subsequently, we designed a non-invasive 40?Hz light-flickering regime that reduced Aß1–40 and Aß1–42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer’s-disease-associated pathology.