Abstract
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.
Keywords:
Arachidonic Acid; Endocannabinoids; Lipid-binding Protein; Lipids; Peroxisome Proliferator-activated Receptor (PPAR).
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Arachidonic Acids / metabolism*
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Blotting, Western
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Brain / metabolism
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Brain / physiology*
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cognition / physiology*
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Endocannabinoids / metabolism*
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Fatty Acid-Binding Proteins / genetics
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Fatty Acid-Binding Proteins / metabolism*
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Gene Regulatory Networks
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Maze Learning / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Microscopy, Confocal
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Oligonucleotide Array Sequence Analysis
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PPAR delta / agonists
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PPAR delta / genetics
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PPAR delta / metabolism*
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PPAR-beta / agonists
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PPAR-beta / genetics
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PPAR-beta / metabolism*
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Polyunsaturated Alkamides / metabolism*
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Protein Binding
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Reverse Transcriptase Polymerase Chain Reaction
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Thiazoles / pharmacology
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Transcriptome / drug effects
Substances
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Arachidonic Acids
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Endocannabinoids
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Fabp5 protein, mouse
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Fatty Acid-Binding Proteins
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Neoplasm Proteins
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PPAR delta
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PPAR-beta
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Polyunsaturated Alkamides
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Thiazoles
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(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
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anandamide