Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB and CB 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 CB and CB receptors, which may form heteromeric complexes (CB-CBHets) 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. In activated microglia mRNA transcripts increased (2 fold for CB and circa 20 fold for CB), whereas receptor levels were similar for CB and markedly upregulated for CB; CB-CBHets were also upregulated. Unlike in resting cells, CB receptors became robustly coupled to G in activated cells, in which CB-CBHets mediated a potentiation effect. Hence, resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß). Microglial activation 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) 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 and in cells from control animals activated using LPS plus IFN-γ. Expression of CB-CBHets 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 CB-CBHet 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 CB-CB heteroreceptor complex in activated microglia have potential as targets in the treatment of neurodegenerative diseases.