Cannabinoid 1 receptor signaling on GABAergic neurons influences astrocytes in the ageing brain

PLoS One. 2018 Aug 16;13(8):e0202566. doi: 10.1371/journal.pone.0202566. eCollection 2018.

Abstract

Astrocytes, key regulators of brain homeostasis, interact with neighboring glial cells, neurons and the vasculature through complex processes involving different signaling pathways. It is not entirely clear how these interactions change in the ageing brain and which factors influence astrocyte ageing. Here, we investigate the role of endocannabinoid signaling, because it is an important modulator of neuron and astrocyte functions, as well as brain ageing. We demonstrate that mice with a specific deletion of CB1 receptors on GABAergic neurons (GABA-Cnr1-/- mice), which show a phenotype of accelerated brain ageing, affects age-related changes in the morphology of astrocytes in the hippocampus. Thus, GABA-Cnr1-/- mice showed a much more pronounced age-related and layer-specific increase in GFAP-positive areas in the hippocampus compared to wild-type animals. The number of astrocytes, in contrast, was similar between the two genotypes. Astrocytes in the hippocampus of old GABA-Cnr1-/- mice also showed a different morphology with enhanced GFAP-positive process branching and a less polarized intrahippocampal distribution. Furthermore, astrocytic TNFα levels were higher in GABA-Cnr1-/- mice, indicating that these morphological changes were accompanied by a more pro-inflammatory function. These findings demonstrate that the disruption of endocannabinoid signaling on GABAergic neurons is accompanied by functional changes in astrocyte activity, which are relevant to brain ageing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Aging / pathology
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • GABAergic Neurons / metabolism*
  • GABAergic Neurons / pathology
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Mice, Knockout
  • Receptor, Cannabinoid, CB1 / genetics*
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / genetics*

Substances

  • CNR1 protein, mouse
  • Receptor, Cannabinoid, CB1
  • Tumor Necrosis Factor-alpha

Grant support

This work was financed by grants from the German Research Council (FOR926 CP1 to AZ, FOR926 SP2 and BI-1227/5-1 to ABG) and from the BONFOR program of the University of Bonn Medical Center (to OA). A.Z. is a member of the DFG-funded Excellence-Cluster ImmunoSensation.