arachidonic-acid and anandamide

Endocannabinoids modulate multiple behaviors, including learning and memory. We show that the endocannabinoid anandamide (AEA) can alter neuronal cell function both through its established role in activation of the G-protein-coupled receptor CB1, and by serving as a precursor for a potent agonist of the nuclear receptor PPARβ/δ, in turn up-regulating multiple cognition-associated genes. We show further that the fatty acid-binding protein FABP5 controls both of these functions in vivo. FABP5 both promotes the hydrolysis of AEA into arachidonic acid and thus reduces brain endocannabinoid levels, and directly shuttles arachidonic acid to the nucleus where it delivers it to PPARβ/δ, enabling its activation. In accordance, ablation of FABP5 in mice results in excess accumulation of AEA, abolishes PPARβ/δ activation in the brain, and markedly impairs hippocampus-based learning and memory. The data indicate that, by controlling anandamide disposition and activities, FABP5 plays a key role in regulating hippocampal cognitive function.

Topics: Active Transport, Cell Nucleus; Animals; Arachidonic Acids; Blotting, Western; Brain; Cell Line, Tumor; Cell Nucleus; Cognition; Endocannabinoids; Fatty Acid-Binding Proteins; Gene Regulatory Networks; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Polyunsaturated Alkamides; PPAR delta; PPAR-beta; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; Thiazoles; Transcriptome

TASK-1 encodes an acid- and anaesthetic-sensitive background K(+) current, which sets the resting membrane potential of both cerebellar granule neurons and somatic motoneurons. We demonstrate that TASK-1, unlike the other two pore (2P) domain K(+) channels, is directly blocked by submicromolar concentrations of the endocannabinoid anandamide, independently of the CB1 and CB2 receptors. In cerebellar granule neurons, anandamide also blocks the TASK-1 standing-outward K(+) current, IKso, and induces depolarization. Anandamide-induced neurobehavioural effects are only partly reversed by antagonists of the cannabinoid receptors, suggesting the involvement of alternative pathways. TASK-1 constitutes a novel sensitive molecular target for this endocannabinoid.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cannabinoids; Cerebellum; Chlorocebus aethiops; COS Cells; Endocannabinoids; Halothane; Humans; Membrane Potentials; Mice; Motor Neurons; Nerve Tissue Proteins; Neurons; Piperidines; Polyunsaturated Alkamides; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Tandem Pore Domain; Pyrazoles; Rats; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Recombinant Proteins; Rimonabant; Transfection