Microglia are key to maintaining the homeostasis of the brain. These immune cells of the brain can be our biggest ally in fighting infections, but can worsen pathology or hinder recovery when uncontrolled. Thus, understanding how microglia contribute to neuroinflammatory processes and how their activity can be controlled is of great importance. It is known that activation of endocannabinoid system, and especially the cannabinoid type 2 receptor (CB2R), decreases inflammation. Alongside its non-psychoactive effect, it makes the CB2R receptor a perfect target for treating diseases accompanied by neuroinflammation including neurodegenerative diseases. However, the exact mechanisms by which CB2R regulates microglial activity are not yet understood. Here, we review the current knowledge on the roles of microglial CB2R from in vitro and in vivo studies. We look into CB2R function under physiological and pathological conditions and focus on four different disease models representing chronic and acute inflammation. We highlight open questions and controversies and provide an update on the latest discoveries that were enabled by the development of novel technologies. Also, we discuss the recent findings on the role of microglia CB2R in cognition and its role in neuron–microglia communication.

Highlights d Relative astrocytic coverage of glutamatergic spines decreases with spine size d Control of perisynaptic glutamate transients by uptake decreases with spine size d Control of receptor-mediated Ca 2+ entry by uptake decreases with spine size d Accordingly, small spines are better shielded from invading glutamate

The tight regulation of microglia activity is key for precise responses to potential threats, while uncontrolled and exacerbated microglial activity is neurotoxic. Microglial toll‐like receptors (TLRs) are indispensable for sensing different types of assaults and triggering an innate immune response. Cannabinoid receptor 2 (CB2) signaling is a key pathway to control microglial homeostasis and activation, and its activation is connected to changes in microglial activity. We aimed to investigate how CB2 signaling impacts TLR‐mediated microglial activation. Here, we demonstrate that deletion of CB2 causes a dampened transcriptional response to prototypic TLR ligands in microglia. Loss of CB2 results in distinct microglial gene expression profiles, morphology, and activation. We show that the CB2‐mediated attenuation of TLR‐induced microglial activation is mainly p38 MAPK‐dependent. Taken together, we demonstrate that CB2 expression and signaling are necessary to fine‐tune TLR‐induced activation programs in microglia.

Physiological brain aging is characterized by gradual, substantial changes in cognitive ability, accompanied by chronic activation of the neural immune system. This form of inflammation, termed inflammaging, in the central nervous system is primarily enacted through microglia, the resident immune cells. The endocannabinoid system, and particularly the cannabinoid receptor 2 (CB2R), is a major regulator of the activity of microglia and is upregulated under inflammatory conditions. Here, we elucidated the role of the CB2R in physiological brain aging. We used CB2R−/− mice of progressive ages in a behavioral test battery to assess social and spatial learning and memory. This was followed by detailed immunohistochemical analysis of microglial activity and morphology, and of the expression of pro-inflammatory cytokines in the hippocampus. CB2R deletion decreased social memory in young mice, but did not affect spatial memory. In fact, old CB2R−/− mice had a slightly improved social memory, whereas in WT mice we detected an age-related cognitive decline. On a cellular level, CB2R deletion increased lipofuscin accumulation in microglia, but not in neurons. CB2R−/− microglia showed an increase of activity markers Iba1 and CD68, and minor upregulation in tnfa and il6 expression and downregulation of ccl2 with age. This was accompanied by a change in morphology as CB2R−/− microglia had smaller somas and lower polarity, with increased branching, cell volume, and tree length. We present that CB2Rs are involved in cognition and age-induced microglial activity, but may also be important for microglial activation itself.