Astrocytic FABP5 mediates retrograde endocannabinoid transport at central synapses

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Endocannabinoids (eCBs) are key lipid mediators regulating synaptic plasticity.
• The precise mechanisms governing eCB synaptic transport remain largely unknown.
• Fatty acid binding proteins (FABPs) are implicated in lipid transport, but their role in eCB signaling is unclear.

Purpose of the Study:

• To investigate the role of Fatty Acid Binding Protein 5 (FABP5) in endocannabinoid (eCB) synaptic transport.
• To elucidate the cellular origin and mechanism of FABP5-mediated eCB transport.

Main Methods:

• Utilized knockout mice lacking FABP5 (FABP5 KO) to study depolarization-induced suppression of inhibition (DSI) in the hippocampus.
• Employed rescue experiments with wild-type and mutant FABP5, including astrocytic-specific re-expression and secreted variants.
• Assessed the contribution of neuronal and astrocytic FABP5 to eCB signaling.

Main Results:

• Deletion of FABP5 significantly impaired DSI, indicating a role in retrograde eCB signaling.
• Re-expression of wild-type FABP5, but not a 2-AG binding-deficient mutant, rescued DSI.
• Astrocytic FABP5, but not neuronal FABP5, was essential for DSI, and its secretion was critical for function.

Conclusions:

• Extracellular FABP5, particularly from astrocytes, is essential for regulating 2-arachidonoylglycerol (2-AG) transport.
• FABP5 plays a dual role in coordinating both intracellular and synaptic endocannabinoid transport.
• These findings reveal a novel mechanism for synaptic eCB transport mediated by astrocytic FABP5.