Periodic Reporting for period 2 - MiCaBra (Mitochondrial Cannabinoid Receptors in the Brain)
Reporting period: 2020-05-01 to 2021-10-31
Thus, MiCaBra aims at detailing and deeply investigationg the potential roles of mtCB1 receptors, starting from a biochemical/cell biology point of view, up to addressing their behavioral implications.
Considering the importance of CB1 receptors as the main targets of the plant cannabis sativa and as the main effector of the phyisiological endocannabinoid system, understanding their different modes of action is very important not only to better understand the mechanisms of brain functions, but also towards the development of novel therapeutic approaches for different conditions. Indeed, cannabis and cannabinoids are endowed with very interesting therapeutic potentials (analgesia, antispasm, anxiolytic, etc), but a certain number important possible side effects (amnesia, psychotic-like reponses, addiction potential, etc) limit their use in clinical settings and constitute the danger associated with their recreational use. As you can see below, our studies started addressing these issues, by demonstratin, for instance, that antisocial cannabinoid-induced behavior is specifically due to mtCB1 in astrocytes of specific brain regions. Moreover, we were recently able to differentiate the impact of pmCB1 and mtCB1 in the same neuronal circuit.
Jimenez-Blasco et al. 2020 (Nature) Glucose metabolism links astroglial mitochondria to cannabinoid effects.
Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses. By contrast, astrocytes are under neuronal control through specific neurotransmitter receptors. However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse mtCB1 receptors hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB1 receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB1 receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice (Image 1)
Soria-Gomez et al. 2021 (Neuron) Subcellular specificity of cannabinoid effects in striatonigral circuits.
Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associatedCB1 receptors (mtCB1) located at thesame terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior (Image 2).