A cannabinoid link between mitochondria and memory

Cannabinoids affect CB 1 receptors on the mitochondrial membranes in the brain, triggering a decrease in downstream cAMP-dependent signalling; this leads to a decrease in brain mitochondrial activity and to cannabinoid-induced amnesia. Bioenergetics deficiency and memory The pathological effect of chronic mitochondrial dysfunction on cognitive function is well established, however the acute modulation of neural processing by mitochondrial signalling is less well understood. These authors demonstrate that acute functional disruption of the brain by cannabinoids involves the activation and signalling from mitochondrial cannabinoid receptors. Thus, even acute mitochondrial bioenergetic changes or disruption can have a short-term effect on cognition, underscoring the role that mitochondria have in regulating normal brain activity. Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP 1 , 2 , 3 , 4 . Acute cannabinoid intoxication induces amnesia in humans and animals 5 , 6 , and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB 1 ) can directly alter mitochondrial energetic activity 7 , 8 , 9 . Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established 1 , 2 , the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB 1 receptors. Genetic exclusion of CB 1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB 1 receptors signal through intra-mitochondrial Gα i protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB 1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to m