Nature: The mitochondria of astrocytes control social behavior through cannabinoids.

Learn about the latest progress in neuroscience ● click the blue letter to pay attention to us ● the "bully president" neurons in the brain consume 80 – 90% of the total energy consumed by the brain (1). In order to provide sufficient energy, smart neurons choose the most effective and fastest way to generate ATP - oxidative phosphorylation pathway to provide energy.as the most widely distributed astrocytes, astrocytes can only meet their energy needs through glycolysis.what is more tragic is that it actually absorbs glucose from the blood, not mainly for itself, but to provide energy for neuron activities. From this perspective, astrocytes have a strong sense of dedication and dare to sacrifice.in the brain, lactic acid is formed in astrocytes by glucose or glycogen and then transferred to neurons rapidly. Therefore, there is a close metabolic coupling between neurons and astrocytes.previous studies have shown that activation of the brain mitochondrial membrane associated cannabinoid receptor 1 (mtcb1) directly regulates mitochondrial energy activity.in 2016, Giovanni Marsicano research team of University of Bordeaux, France, first revealed the relationship between cannabinoid receptor on mitochondria and memory: cannabinoid receptor 1 related to hippocampal mitochondrial membrane regulates acute hemp induced memory impairment, and knockout of this receptor on neurons can reverse memory impairment (2).four years later, on July 9, 2020, the king returned. Professor Giovanni Marsicano published an article in the journal Nature, revealing that mtcb1 can directly regulate glucose metabolism in astrocytes, thus affecting the social behavior of mice.the researchers found that mtcb1 was expressed in hippocampus, prefrontal cortex and nucleus accumbens, but the content of mtcb1 receptor in astrocytes was higher than that in neurons.in vitro experiments showed that the activity of mitochondrial respiratory chain complex 1 (complex 1) decreased in primary cultured astrocytes after incubation with cannabinoid (THC) and permeable CB 1 receptor agonist hu201 in a dose-dependent manner.at the same time, the expression of N-terminal skeleton protein subunits NDUFS1 and ndufv2 of the assembly module of complex 1 decreased, indicating that the structure of complex 1 was unstable. However, there was no decrease in CB1 receptor knockout mice.Fig. 1, expression of mtcb1 receptor in different brain regions and different types of nerve cells. After a dose of cannabinoid, the expression of mitochondrial structural proteins NDUFS1 and ndufv2 in hippocampus and prefrontal cortex decreased, and the stability of mitochondrial complex 1 decreased.however, after specific knockout of astrocytes CB1 receptor (hereinafter referred to as gfap-cb1-ko mice) did not show the above-mentioned decrease.these results indicate that the structure of CB1 receptor complex I in activated astrocytes is unstable.Why are the structures of these complexes 1 unstable under the action of cannabinoid? They anchored the suspect to the ndufs4 subunit ser173, which phosphorylation determines the stability and assembly of the N-module of complex 1.hu201 and cannabinoid could reduce the phosphorylation of ser173 of ndufs4 subunit, which could be blocked by CB 1 receptor antagonist.this decrease did not occur in CB1 receptor knockout mice. In addition, the phosphorylation level of ser173 of ndufs4 subunit in gfap-cb1-ko mice was significantly higher than that in wild-type mice, indicating that dephosphorylation of ndufs4 subunit ser173 is involved in the activation of CB1 receptor in astrocytes.the researchers also gave the mice a dose of cannabinoid, which increased the apoptosis of neurons in hippocampus and prefrontal cortex and the reactive oxygen species in mitochondria of wild-type mice. however, after intraperitoneal injection of lactic acid, the apoptosis of the above neurons was completely reversed. in fact, under normal conditions, there was no difference in the rate of glucose conversion into lactic acid between wild mice and gfap-cb1-ko mice. However, after intraperitoneal injection of cannabinoid, the conversion rate of wild mice was significantly reduced, while that of gfap-cb1-ko mice was normal, which indicated that cannabinoid reduced glucose conversion through CB1 receptor of astrocytes. what effect does the magical cannabinoid have on the behavior of mice? Twenty four hours after the intraperitoneal injection of cannabinoid, the researchers conducted a number of behavioral tests on wild-type mice and found that the mice did not show anxiety like behavior disorder, but showed social disorder. however, the social behavior of gfap-cb 1-ko mice was normal. intraperitoneal injection of lactic acid can alleviate the social disorder caused by cannabinoid, which is similar to the effect of CB1 receptor knockout. in general, cannabinoid can destabilize the structure of mitochondrial complex 1 of astrocytes by reducing the phosphorylation of ser173 of ndufs4 subunit, inhibit the conversion of glucose to lactic acid, and cause social disorder. This mechanism depends on the CB1 receptor of astrocytes. References: 1. Howarth, C., Gleeson, P. & amp; Attwell, D. updated energy budget for neural computation in the neocortex and cerebellum. J. cereb. Blood flow Metab. 32, 1222 – 1232 (2012). 2. A cannabinoid link between mitochondria and memory3,