Fatty Acid-binding Protein 5 (FABP5) Regulates Cognitive Function Both by Decreasing Anandamide Levels and by Activating the Nuclear Receptor Peroxisome Proliferatoractivated Receptor β/δ(PPARβ/δ) in the Brain

Background: FABP5 shuttles ligands to the nuclear receptor PPAR/ and enhances degradation of the endocannabinoid anandamide. Results: Brain level of anandamide is high and PPAR/ activation is low in FABP5-null mice. These mice display impaired learning and memory. Conclusion: FABP5 regulates learning and memory by two distinct mechanisms. Significance: The data suggest that FABP5 may be a novel target for therapy of cognitive dysfunction. 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 PPAR/, 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 PPAR/, enabling its activation. In accordance, ablation of FABP5 in mice results in excess accumulation of AEA, abolishes PPAR/ 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.