Misbalance in metabolism

Astrocytes provide metabolic support to neurons by metabolizing glucose to produce lactate, which neurons use for energy. owever, whether and how changes in astrocytic metabolism can affect neurons and behaviour is not clear. Now, Jimenez-Blasco et al. show in mice that activation of the mitochondrial membrane cannabinoid 1 receptor (mtCB₁) in astrocytes disrupts the metabolism of these cells and neurons, and induces deficits in social behaviour.

The authors identified CB₁ in juxtaposition with astrocytic mitochondria. Treating cultured mouse astrocytes with a cell-permeable CB₁ agonist (HU210 or THC), but not a cell-impermeable CB₁ agonist, reduced mitochondrial complex I activity. This effect was restored in CB₁-null astrocytes by re-expressing wild-type (WT) CB₁, but not a form of CB₁ excluded from mitochondria. Thus, mtCB₁ activation reduces astrocyte metabolism through complex I.

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In WT astrocytes and mouse brains, HU210 and THC reduced Ser173 phosphorylation of the complex I subunit NDUFS4 (NADH dehydrogenase (ubiquinone) iron-sulphur protein 4). By contrast, THC did not reduce NDUFS4 phosphorylation in CB₁-null astrocytes. In addition, complex I function in astrocytes expressing a phosphomimetic form of NDUFS4 (NDUFS4-PM) was unaffected by CB₁ agonism. The authors also showed that NDUFS4 Ser173 phosphorylation is needed for complex I stability, thus indicating that CB₁ activation destabilizes complex I by reducing NDUFS4 phosphorylation.

Previous research suggests that mitochondrial reactive oxygen species (mROS) generated by complex I are sensed by hypoxia-inducible factor 1 (HIF1), which in turn promotes glycolysis and lactate release. Here, THC reduced mROS production, HIF1 subunit levels and lactate release in WT, but not NDUFS4-PM-expressing or CB₁-null, astrocytes. Moreover, neurons co-cultured with WT astrocytes that had previously been treated with THC or HU210 showed signs of bioenergetic stress that were ameliorated by lactate supplementation. Thus, astrocyte CB₁ agonism disrupts the glycolytic support that astrocytes provide to neurons.

Next, the authors tested the effects of astrocyte CB₁ activation on behaviour in two social interaction tasks. THC injection led to deficits in the two-chamber social interaction test in WT mice but not in mice lacking CB₁ in astrocytes or in WT mice that had received an intracerebroventricular injection of lactate. Knockdown of monocarboxylate transporter 2 (which carries lactate into neurons) in the hippocampus and prefrontal cortex of mice also occluded the effects of THC treatment on social interactions, implying that the behavioural effects of astrocyte CB₁ agonism are mediated by a reduction in the supply of lactate to neurons.

CB₁ activation destabilizes complex I

Together, these findings demonstrate that activation of astrocyte mtCB₁ induces metabolic disruption in astrocytes and neurons, resulting in behavioural changes.