Cannabinoid Receptors Modulate Physiological Remodelling of the Blood-Testis Barrier

The endocannabinoid system, including the CB1 and CB2 receptors, has been associated with the modulation of blood-brain barrier and gut barrier. Herein, using CB1 knock-out male mice, we studied the potential role of these receptors in maintenance of blood-testis barrier (BTB) integrity during the seminiferous epithelium remodelling phase (Stages VIII-XI), focusing on events responsive to CB1 and CB2 activity. Our results showed that the genetic loss of CB1 disrupted testicular expression of some components of BTB, including factors of junctional complexes, promoting tubular infiltration of blood cells. Such infiltration specifically occurred at Stages VIII-IX transition. Gene expression analysis of molecular tags that highlight BTB remodelling (by addressing Occludin to early/late endosome, membrane recycling and proteasome) revealed higher BTB dynamism and impoverishment of tight junctions at Sertoli-Sertoli interface with significant effects on BTB remodelling activities. In detail, CB1 deletion increased kinetic of internalization and recycling of tight junctions and simultaneously promoted proteosome-mediated Occludin degradation with negative effects on permeability of BTB during its remodelling. This caused the leakage of the tight junctions, the premature passage of germ cells in adluminal compartment and downstream the slowing of spermatogenesis. These results strongly indicated that CB1 and CB2 activation contribute to BTB remodelling being both involved in the modulation of tight junction-associated proteins and in their dynamism: these data highlight a new role for CB1 in spermatogenesis.