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Background  The cannabinoid CB 2  receptor (CB 2 R), which is a target to afford neuroprotection, and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, which are key in mediating excitatory neurotransmission, are expressed in both neurons and glia. As NMDA receptors are the target of current medication in Alzheimer’s disease patients and with the aim of finding neuromodulators of their actions that could provide benefits in dementia, we hypothesized that cannabinoids could modulate NMDA function.    Methods  Immunocytochemistry was used to analyze the colocalization between CB 2  and NMDA receptors; bioluminescence resonance energy transfer was used to detect CB 2 -NMDA receptor complexes. Calcium and cAMP determination, mitogen-activated protein kinase (MAPK) pathway activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify CB 2 -NMDA heteromer expression in mouse primary cultures and in the brain of APP Sw/Ind  transgenic mice, an Alzheimer’s disease model expressing the Indiana and Swedish mutated version of the human amyloid precursor protein (APP).    Results  In a heterologous system, we identified CB 2 -NMDA complexes with a particular heteromer print consisting of impairment by cannabinoids of NMDA receptor function. The print was detected in activated primary microglia treated with lipopolysaccharide and interferon-γ. CB 2 R activation blunted NMDA receptor-mediated signaling in primary hippocampal neurons from APP Sw/Ind  mice. Furthermore, imaging studies showed that in brain slices and in primary cells (microglia or neurons) from APP Sw/Ind  mice, there was a marked overexpression of macromolecular CB 2 -NMDA receptor complexes thus becoming a tool to modulate excessive glutamate input by cannabinoids.    Conclusions  The results indicate a negative cross-talk in CB 2 -NMDA complexes signaling. The expression of the CB 2 -NMDA receptor heteromers increases in both microglia and neurons from the APP Sw/Ind  transgenic mice, compared with levels in samples from age-matched control mice.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13195-021-00920-6.

alzheimer's research and therapy

N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors