A cannabinoid link between mitochondria and memory

Abstract

Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, 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 receptors. Genetic exclusion of CB receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB receptors signal through intra-mitochondrial Gα 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 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.

An energetic view of stress: Focus on mitochondria

“…The CB1 receptor, which localize at the plasma membrane of the presynaptic terminal, is also found in mitochondria (Benard et al, 2012). Upon activation, mitochondrial CB1 can decrease mitochondrial oxidative capacity and modulate memory in a mitochondria-dependent manner (Hebert-Chatelain et al, 2016). Thus, as discussed in the next section, glucocorticoids and other systemic signaling molecules may converge upon mitochondria to induce systemic changes in the metabolism of the brain and multiple other tissues.…”

Cannabinoid Receptor Signaling in Central Regulation of Feeding Behavior: A Mini-Review

“…By interfering with respiratory chain complex I, mitochondrial CB 1 was recently shown to promote the amnesia-inducing effects of CB 1 agonists in the hippocampus (Hebert-Chatelain et al, 2016; Harkany and Horvath, 2017). Accordingly, effects of cannabinoids on food intake are also transmitted via CB 1 -induced mitochondrial adaptations, since induction of feeding by CB 1 agonists depended on the expression of mitochondrial uncoupling protein 2 and the formation of reactive oxygen species (ROS) in the hypothalamus (Koch et al, 2015; Kruger, 2016), finally pointing toward region-specific functions of mitochondrial CB 1 signaling in the brain (Harkany and Horvath, 2017).…”

Intracellular GPCRs Play Key Roles in Synaptic Plasticity

“…Short term consequences of mitochondrial CB 1 receptor signaling include synaptic depression; long term consequences can include memory loss (77), metabolic defects and apoptosis (78). Current data suggest that mitochondrial CB 1 receptors are coupled to Gα i which appears to inhibit soluble adenylyl cyclase within the mitochondrial matrix (77). Interestingly, cell surface, presynaptic CB 1 receptors remain unchanged (77).…”

“…Current data suggest that mitochondrial CB 1 receptors are coupled to Gα i which appears to inhibit soluble adenylyl cyclase within the mitochondrial matrix (77). Interestingly, cell surface, presynaptic CB 1 receptors remain unchanged (77). …”

“…Although pharmacological isolation provides evidence of a given receptor’s in vivo physiological role, the development of genetically isolated animals in which receptors are targeted or excluded from a given intracellular membrane, would reinforce the role of an intracellular receptor. For example, Hebert-Chatelain et al (77) discovered that removal of the first 22 amino acids at the N-terminus of CB 1 receptors (DN22-CB 1 ) prevents the receptor from going to or affecting mitochondrial processes such as respiration or mobility. Genetic isolation in vivo via viral re-expression of CB 1 and DN22-CB 1 in CB 1 knock out animals revealed that only mitochondrial CB 1 receptors mediated hippocampal synaptic transmission and memory formation.…”