Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons Influences Microglial Activity

Abstract

Microglia, the resident immune cells of the brain, play important roles in defending the brain against pathogens and supporting neuronal circuit plasticity. Chronic or excessive pro-inflammatory responses of microglia damage neurons, therefore their activity is tightly regulated. Pharmacological and genetic studies revealed that cannabinoid type 1 (CB1) receptor activity influences microglial activity, although microglial CB1 receptor expression is very low and activity-dependent. The CB1 receptor is mainly expressed on neurons in the central nervous system (CNS)—with an especially high level on GABAergic interneurons. Here, we determined whether CB1 signaling on this neuronal cell type plays a role in regulating microglial activity. We compared microglia density, morphology and cytokine expression in wild-type (WT) and GABAergic neuron-specific CB1 knockout mice (GABA/CB1−/−) under control conditions (saline-treatment) and after 3 h, 24 h or repeated lipopolysaccharide (LPS)-treatment. Our results revealed that hippocampal microglia from saline-treated GABA/CB1−/− mice resembled those of LPS-treated WT mice: enhanced density and larger cell bodies, while the size and complexity of their processes was reduced. No further reduction in the size or complexity of microglia branching was detected after LPS-treatment in GABA/CB1−/− mice, suggesting that microglia in naïve GABA/CB1−/− mice were already in an activated state. This result was further supported by correlating the level of microglial tumor necrosis factor α (TNFα) with their size. Acute LPS-treatment elicited in both genotypes similar changes in the expression of pro-inflammatory cytokines (TNFα, interleukin-6 (IL-6) and interleukin 1β (IL-1β)). However, TNFα expression was still significantly elevated after repeated LPS-treatment in WT, but not in GABA/CB1−/− mice, indicating a faster development of tolerance to LPS. We also tested the possibility that the altered microglia activity in GABA/CB1−/− mice was due to an altered expression of neuron-glia interaction proteins. Indeed, the level of fractalkine (CX3CL1), a neuronal protein involved in the regulation of microglia, was reduced in hippocampal GABAergic neurons in GABA/CB1−/− mice, suggesting a disturbed neuronal control of microglial activity. Our result suggests that CB1 receptor agonists can modulate microglial activity indirectly, through CB1 receptors on GABAergic neurons. Altogether, we demonstrated that GABAergic neurons, despite their relatively low density in the hippocampus, have a specific role in the regulation of microglial activity and cannabinoid signaling plays an important role in this arrangement.

Systemic inflammation impairs microglial Aβ clearance through NLRP 3 inflammasome

“…For quantitative analysis, two‐photon Z ‐stacks were automatically reconstructed using a self‐customized python‐based script (Ativie et al , ). Reconstructions were visually checked using the ImageJ plugin “simple neurite tracer” (Appendix Fig S6).…”

CB2 Receptor in Microglia: The Guardian of Self-Control

“…Neuronal loss during neurodegeneration and consequent loss of these interacting surface proteins activates microglia, thus CX3CR1 is believed to be neuroprotective in neurodegenerative diseases [151]. We are not aware of any studies that directly investigated CB2R-mediated neuron-microglia interaction, but we have previously shown that CB1Rs on GABAergic neurons play a role in neuron-microglia communication via fractalkine/CX3CR1 [153]. Moreover, AEA, and possibly 2-AG as well, can be secreted via microglial extracellular membrane vesicles and by activating CB1R inhibit synaptic transmission of GABAergic neurons [154] (Figure 2).…”

A Guide to Targeting the Endocannabinoid System in Drug Design

“…Endocannabinoid signaling may also be beneficial because of its impact on attenuating neurotoxicity and neuroinflammation. It has been shown that deletion of CB1 accelerates brain aging through tumor necrosis factor α (TNF-α) [166], while CB1 agonism decreases neuroinflammation [167]. There have also been studies on FAAH inhibition impact on decreasing neuroinflammation [168] and exitoxicity in rodent models [169].…”