Astrocytic FABP5 mediates retrograde endocannabinoid transport at central synapses

Endocannabinoids (eCBs) regulate synaptic function via cannabinoid receptors. While eCB signaling is well understood, the mechanisms underlying eCB synaptic transport are poorly characterized. Using 2-arachidonoylglycerol (2-AG)-mediated depolarization-induced suppression of inhibition (DSI) in the hippocampus as a readout of retrograde eCB signaling, we demonstrate that the deletion of fatty acid binding protein 5 (FABP5) impairs DSI. In FABP5 KO mice, DSI was rescued by re-expressing wild-type FABP5 but not an FABP5 mutant that does not bind 2-AG. Importantly, the deletion of astrocytic FABP5 blunted DSI, which was rescued by its re-expression in the astrocytes of FABP5 KO mice. Neuronal FABP5 was dispensable for 2-AG signaling. DSI was also rescued by expressing a secreted FABP5 variant but not by FABP7, an astrocytic FABP that does not undergo secretion. Our results demonstrate that extracellular FABP5 of astrocytic origin controls 2-AG transport and that FABP5 is adapted to coordinate intracellular and synaptic eCB transport.