Cannabinoid Signaling Plays Role In Regulation Of Microglial Activity

The cannabinoid 1 receptor appears to act as a kind of “sensor” with which neurons measure and control the activity of certain immune cells in the brain, a recent study from the University of Bonn indicates. If this sensor function fails, chronic inflammation may result — probably representing the beginning of a dangerous vicious circle.

The so-called CB1 receptor is responsible for the intoxicating effect of cannabis. Pharmacological studies have also shown a significant effect of cannabinoids on microglial activity.

The activity of microglial cells plays an important role in brain aging. These cells are part of the brain’s immune defense; they detect and digest bacteria, for example, but also eliminate diseased or defective nerve cells. They also use messenger substances to alert other defense cells and thus initiate a concerted campaign to protect the brain: an inflammation.

Inflammatory Brake Signals

This protective mechanism has undesirable side effects — it can also cause damage to healthy brain tissue. Inflammations are therefore usually strictly controlled.

“We know that so-called endocannabinoids play an important role in this. These are messenger substances produced by the body that act as a kind of brake signal. They prevent the inflammatory activity of the glial cells.”

explained Dr. Andras Bilkei-Gorzo from the Institute of Molecular Psychiatry at the University of Bonn.

Endocannabinoids develop their effect by binding to special receptors. There are two different types called CB1 and CB2.

“However, microglial cells have virtually no CB1 and a very low level of CB2 receptors. And yet they react to the corresponding brake signals. Why this is the case has been puzzling so far,”

said Bilkei-Gorzo.

Middlemen Neurons

The scientists at the University of Bonn have now been able to shed light on this puzzle. Their findings indicate that the brake signals do not communicate directly with the glial cells, but via middlemen — a certain group of neurons, because this group has a large number of CB1 receptors.

“We have studied laboratory mice in which the receptor in these neurons was switched off,” explained Bilkei-Gorzo. “The inflammatory activity of the microglial cells was permanently increased in these animals.”

In contrast, in control mice with functional CB1 receptors, the brain’s own defense forces were normally inactive.

Representative microphotograph of Iba1 immunostaining (red) and DAPI fluorescence showing cell nuclei

(A) Representative microphotograph of Iba1 immunostaining (red) and DAPI fluorescence showing cell nuclei (blue) in the hippocampus of WT and GABA/CB1−/− mice 24 h after four times daily intraperitoneal LPS injections.
(I) Low magnification image, the scale bar represents 100 μm. White quadrant shows the region presented as high magnification image.
(II) High magnification image, the scale bar represents 25 μm. so—stratum oriens; sp—stratum pyramidale; sr—stratum radiatum; slm—stratum lacunosum moleculare; sg—stratum granulosum. Density of Iba1-positive (Iba1+) microglia cells in the hippocampus of WT and GABA/CB1−/− mice
(B) Three hours after an intraperitoneal LPS-treatment.
(C) Twenty-four hours after an intraperitoneal LPS-treatment.
(D) Twenty-four hours after four times daily intraperitoneal LPS injections. **p < 0.01; ***p < 0.001 difference between saline and LPS-treated mice using Bonferroni’s t-test. ++p < 0.01; +++p < 0.001 difference between WT and GABA/CB1−/− mice with the same treatment using Bonferroni’s t-test. +p < 0.05.
Credit: Ativie, et al CC-BY

This only changed in the present of inflammatory stimulus.

“Based on our results, we assume that CB1 receptors on neurons control the activity of microglial cells. However, we cannot yet say whether this is also the case in humans,”

said Bilkei-Gorzo.

Inflammation Mode On

This is how the mechanism might work in mice.

As soon as microglial cells detect a bacterial attack or neuronal damage, they switch to inflammation mode. They produce endocannabinoids, which activate the CB1 receptor of the neurons in their vicinity. This way, they inform the nerve cells about their presence and activity.

The neurons may then be able to limit the immune response. The scientists were able to show that neurons similarly regulatory the other major glial cell type, the astroglial cells.

During ageing the production of cannabinoids declines reaching a low level in old individuals. This could lead to a kind of vicious circle, Bilkei-Gorzo suspects:

“Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode. More regulatory neurons die as a result, so the immune response is less regulated and may become free-running.”

It may be possible to break this vicious circle with drugs in the future. It is, for instance, hoped that cannabis will help slow the progression of dementia. It’s ingredient, tetrahydrocannabinol (THC), is a powerful CB1 receptor activator—even in low doses free from intoxicating effect.

Dr. Andras Bilkei-Gorzo

Dr. Andras Bilkei-Gorzo.
Credit: © Kerstin Nicolai/Uni Bonn

Last year, the researchers from Bonn and colleagues from Israel were able to demonstrate that cannabis can reverse the aging processes in the brains of mice. This result now suggest that an anti-inflammatory effect of THC may play a role in its positive effect on the ageing brain.

The research was funded by grants from the German Research Council, and from the BONFOR program of the University of Bonn Medical Center.

Frank Ativie, Joanna A. Komorowska, Eva Beins, Önder Albayram, Till Zimmer, Andreas Zimmer, Dario Tejera, Michael Heneka and Andras Bilkei-Gorzo
Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons Influences Microglial Activity
Front. Mol. Neurosci., 28 August 2018 | https://doi.org/10.3389/fnmol.2018.00295

Top Image: microphotograph of Iba1 immunostaining (red) and DAPI fluorescence showing cell nuclei (blue) in the hippocampus of WT and GABA/CB1−/− mice 24 h after four times daily intraperitoneal LPS injections. Credit: Ativie, et al CC-BY