Role of cannabinoid signalling between neurons and microglia cells in brain ageing

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We have shown previously that there is an early onset of brain ageing accompanied with increased microglial activity in the hippocampus of animals lacking CB1 receptors on GABAergic neurons. This highly unexpected result led us to the hypotheses that (1) endocannabinoid system plays a role as communication channel between GABAergic neurons and microglia and (2) cannabinoid signaling between neurons and microglia is protective against age-related changes. To test these possibilities we will evaluate in a longitudinal study the age-related cognitive and histological changes in mice lacking the main endocannabinoid synthesizing enzyme diacylglycerol lipase (DAGL) alpha and beta from microglia. Our previous results also suggested that reduced signaling between microglia and GABAergic neurons upregulates microglial activity and promotes neuroinflammation in the ageing brain. Thus, we will compare the reactivity of microglia using organotypic hippocampal culture from GABA specific CB1 knockout and microglia specific DAGL alpha and DAGL beta knockout animals. We will also compare the motility and morphology of GFP-tagged microglia transplanted to the hippocampus of wild-type and GABA/CB1-/- mice with different age. Lastly, we hypothesize that disturbed endocannabinoid signalling leads to an early onset and/or exacerbated senescence associated phenotype in microglia. To test this possibility we will compare lipofuscin accumulation, dynamics of epigenetic and gene expression changes and the phenotype of the microglia cells isolated from the brain of wild-type and GABA/CB1-/- animals with different age.