Gamma oscillations attenuate amyloid pathology and trigger a protective microglia response in a mouse model of Alzheimer''s disease

Gamma oscillations (20-50Hz) are a common local field potential signature in many brain regions that are generated by a resonant circuit between fast-spiking parvalbumin (PV)-positive interneurons and pyramidal cells. Changes in the magnitude and frequency of gamma have been observed in several neuropsychiatric disorders. However, it is unclear how disruptions in gamma oscillations affect cellular pathologies seen in these disorders. Here, we investigate this using the 5XFAD mouse model of Alzheimer’s disease (AD) and find reduced power and magnitude of behaviorally driven gamma oscillatory activity — even before the onset of plaque formation or measurable cognitive decline. Because of the early onset, we aimed to determine if exogenous manipulations of gamma could influence the progression of disease pathology. We find that driving PV-positive neurons at gamma frequency (40Hz) using channelrhodopsin-2 reduced total levels of amyloid-ß (Aß) 40 and 42 isoforms in the hippocampus of 5XFAD mouse. Driving PV-positive neurons at other frequencies, or driving excitatory neurons, did not reduce Aß levels. Furthermore, driving PV-positive neurons reduced enlarged endosomes in hippocampal neurons and cleavage intermediates of APP in 5XFAD mouse. Gene expression profiling revealed a neuroprotective response with morphological transformation of microglia and markedly increased phagocytosis of Aß by microglia. Inspired by these observations, we designed a non-invasive light-flickering paradigm that drives 40Hz gamma activity in mouse visual cortex. The light-flickering paradigm profoundly reduced Aß40 and Aß42 levels in the visual cortex of pre-symptomatic mice and greatly mitigated plaque load in the visual cortex of aged, symptomatic mice. This reduction was completely blocked by a GABA-A antagonist, providing further support for an essential role of GABAergic signaling in mediating neuroprotective gamma activity. Overall, our findings uncover a dramatic and previously unappreciated function of the brain’s endogenous gamma rhythms in reducing the production and increasing the clearance of Aß peptides, whose accumulation is believed to drive the pathogenesis of AD. Overall design: Two to four weeks following virus injection and implant placement, hippocampal CA1 neurons were optigenetically manipulated. During the experiment, 1mW of optical stimulation was delivered for 1h using a 40Hz stimulation protocol.

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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