Linking Mitochondria and Synaptic Transmission: The CB1 Receptor

CB1 receptors are functionally present within brain mitochondria (mtCB1), although they are usually considered specifically targeted to plasma membrane. Acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. However, the detailed mechanism linking disrupted mitochondrial metabolism and synaptic transmission is still uncharacterized. CB1 receptors are among the most abundant G protein-coupled receptors in the brain and impact on several processes, including fear coping, anxiety, stress, learning, and memory. Mitochondria perform several key physiological processes for neuronal homeostasis, including production of ATP and reactive oxygen species, calcium buffering, metabolism of neurotransmitters, and apoptosis. It is therefore possible that acute activation of mtCB1 impacts on these different mitochondrial functions to modulate synaptic transmission. In reviewing and integrating across the literature in this area, we describe the possible mechanisms involved in the regulation of brain physiology by mtCB1 receptors.

Activation of mitochondrial CB1 (mtCB1) but not of plasma membrane CB1 (pmCB1) decreases brain mitochondrial activity, glutamatergic synaptic transmission, and memory performance. Several processes can be involved in this alteration of brain physiology, including mitochondrial ATP and ROS production, axonal mitochondrial transport, Ca²⁺ homeostasis, and/or metabolism of the neurotransmitter glutamate.

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