Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia.

Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB₁ and CB₂ receptors, which may form heteromeric complexes (CB₁-CB₂Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoid receptors in resting and LPS/IFN-γ-activated microglia. Unlike CB₁, CB₂ receptors and CB₁-CB₂Hets were upregulated in activated microglia. Resting cell refractory CB₂ receptors became robustly coupled to G_i in activated cells, in which CB₁-CB₂Hets mediated a positive cross-talk. Resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß_1-42). Activation microglial markers were detected in the striatum of a Parkinson’s disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APP_Sw,Ind) mice, a transgenic Alzheimer’s disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APP_Sw,Ind and in cells from control animals activated using LPS plus IFN- γ. Expression of CB₁-CB₂Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment. In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB₁-CB₂Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB₁-CB₂ heteroreceptor complex in activated microglia have potential as targets in the treatment of neurodegenerative diseases.

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