Periodic Reporting for period 4 - MiCaBra (Mitochondrial Cannabinoid Receptors in the Brain)
Okres sprawozdawczy: 2023-05-01 do 2024-10-31
MiCaBra adresses the physiological and pharmacological roles of mitochondria-associated type-1 cannabinoid receptors in the brain (mtCB1). As a G Protein-Coupled Receptor, CB1 is mainly located on the plasma membrane of cells (pmCB1, neurons, astrocytes and others), where it mediates communication between the exterior and the interior of the cell itself. However, some years ago, we discovered that CB1 receptors are also functionally present inside cells, particularly in close association with important iintracellular organs like mitochondria. Here, previous studies from my lab showed that mtCB1 receptors control mitochondrial oxygen consumption and mediate cannabinoid-induced amnesic effects in a novel object recogtnition task.
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.
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.
I can affirm that MiCaBra was a scientific success. During the 5+1 (extension) years of the project 31 papers were published where the support of ERC was instrumental and clearly acknowledged.
Please find below a selected list of the major achievements obtained since 2020, referring to the published studies (asterisks indicate co-authorship).
1. Glucose metabolism links astroglial mitochondria to cannabinoid effects. Jimenez-Blasco D*, Busquets-Garcia A*, Hebert-Chatelain E*, et al... Bolaños JP* and Marsicano* (2020) Nature 583(7817):603-608.
This paper shows that CB1 receptor control glycolysis in astrocytes, determining the production of lactate, and its effect on neuronal functions and social behavior.
2. Specific Hippocampal Interneurons Shape Consolidation of Recognition Memory. Oliveira da Cruz JF, et al... Marsicano G*, Soria-Gómez E* (2020) Cell Rep. 32(7):108046.
This paper shows that a specific subpopulation of hippocampal interneurons co-expressing CB1 and D1 dopamine receptors is necessary for object recognition memory.
3. Subcellular specificity of cannabinoid effects in striatonigral circuits. Soria-Gomez E*, Pagano Zottola A*, Mariani Y*, et al... Marsicano*, Bellocchio L* (2021) Neuron 109(9):1513-1526.e11
This study shows that cataleptic and analgesic effects of cannabinoids require different subcellular populations of CB1 receptors at striatonigral terminals: whereas the cataleptic effects require mtCB1 and reduction of GABAergic transmission, analgesia relies on plasma membrane CB1 and reduction of the release of the neuropeptide Substance P.
4. Astroglial ER-mitochondria calcium transfer mediates endocannabinoid-dependent synaptic integration. Serrat R, et al.... and Marsicano G. (2021) Cell Rep. 21;37(12):110133
This paper shows that mtCB1 promotes the entry of calcium into mitochondria of astrocytes.
5. Mitochondrial cannabinoid receptors gate corticosterone impact on novel object recognition. Skupio U et al.... and Marsicano G. (2023) Neuron. 24:S0896-6273(23)00263-5. doi: 10.1016/j.neuron.2023.04.001.
This paper shows that the memory-impairing effects of stress and corticosterone, require mtCB1 receptors in the hippocampus and mitochondrial calcium regulation.
6. A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice. Fernández-Moncada I et al... and Marsicano G. (2024) Nat Commun. 2024 Aug 9;15(1):6842. doi: 10.1038/s41467-024-51008-2.
This paper shows that CB1 receptors are the link between metabolic and synaptic functions of astrocytes.
7. Olfactory bulb astrocytes link social transmission of stress to cognitive adaptation in male mice. Gómez-Sotres P, et al. and Marsicano G. (2024) Nat Commun. 15(1):7103. doi: 10.1038/s41467-024-51416-4.
This paper shows that social transmission of stress requires mtCB1 receptors in astrocytes of the olfactory bulb
8. Potentiation of mitochondrial activity by mitoDREADD-Gs reverses pharmacological and neurodegenerative impairment of cognition. Pagano Zottola AC, et al... Marsicano G*, Bellocchio L*, Hebert-Chatelain E* (2025) Nat Neurosci. in press
This study presents for the first time a genetic tool (called mitoDREADD), which allows acutely boosting mitochondrial activity, thereby revealing the primary importance of mitochondrial alterations in the cognitive symptoms of cannabinoid intoxication and neurodegenerative diseases.
Please find below a selected list of the major achievements obtained since 2020, referring to the published studies (asterisks indicate co-authorship).
1. Glucose metabolism links astroglial mitochondria to cannabinoid effects. Jimenez-Blasco D*, Busquets-Garcia A*, Hebert-Chatelain E*, et al... Bolaños JP* and Marsicano* (2020) Nature 583(7817):603-608.
This paper shows that CB1 receptor control glycolysis in astrocytes, determining the production of lactate, and its effect on neuronal functions and social behavior.
2. Specific Hippocampal Interneurons Shape Consolidation of Recognition Memory. Oliveira da Cruz JF, et al... Marsicano G*, Soria-Gómez E* (2020) Cell Rep. 32(7):108046.
This paper shows that a specific subpopulation of hippocampal interneurons co-expressing CB1 and D1 dopamine receptors is necessary for object recognition memory.
3. Subcellular specificity of cannabinoid effects in striatonigral circuits. Soria-Gomez E*, Pagano Zottola A*, Mariani Y*, et al... Marsicano*, Bellocchio L* (2021) Neuron 109(9):1513-1526.e11
This study shows that cataleptic and analgesic effects of cannabinoids require different subcellular populations of CB1 receptors at striatonigral terminals: whereas the cataleptic effects require mtCB1 and reduction of GABAergic transmission, analgesia relies on plasma membrane CB1 and reduction of the release of the neuropeptide Substance P.
4. Astroglial ER-mitochondria calcium transfer mediates endocannabinoid-dependent synaptic integration. Serrat R, et al.... and Marsicano G. (2021) Cell Rep. 21;37(12):110133
This paper shows that mtCB1 promotes the entry of calcium into mitochondria of astrocytes.
5. Mitochondrial cannabinoid receptors gate corticosterone impact on novel object recognition. Skupio U et al.... and Marsicano G. (2023) Neuron. 24:S0896-6273(23)00263-5. doi: 10.1016/j.neuron.2023.04.001.
This paper shows that the memory-impairing effects of stress and corticosterone, require mtCB1 receptors in the hippocampus and mitochondrial calcium regulation.
6. A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice. Fernández-Moncada I et al... and Marsicano G. (2024) Nat Commun. 2024 Aug 9;15(1):6842. doi: 10.1038/s41467-024-51008-2.
This paper shows that CB1 receptors are the link between metabolic and synaptic functions of astrocytes.
7. Olfactory bulb astrocytes link social transmission of stress to cognitive adaptation in male mice. Gómez-Sotres P, et al. and Marsicano G. (2024) Nat Commun. 15(1):7103. doi: 10.1038/s41467-024-51416-4.
This paper shows that social transmission of stress requires mtCB1 receptors in astrocytes of the olfactory bulb
8. Potentiation of mitochondrial activity by mitoDREADD-Gs reverses pharmacological and neurodegenerative impairment of cognition. Pagano Zottola AC, et al... Marsicano G*, Bellocchio L*, Hebert-Chatelain E* (2025) Nat Neurosci. in press
This study presents for the first time a genetic tool (called mitoDREADD), which allows acutely boosting mitochondrial activity, thereby revealing the primary importance of mitochondrial alterations in the cognitive symptoms of cannabinoid intoxication and neurodegenerative diseases.
As mentioned above, I consider the study of bioenergetics in the brain and their impact on behavior mandatory to understand basic principles of brain functions in physiology and pathology. Our results represent real breakthroughs, because they establish that bioenergetics is not just a survival mean for brain cells, but it is an important way through which brain cells communicate and behavioral choices are made.