Cannabinoid exposure via lactation in rats disrupts perinatal programming of the GABA trajectory and select early-life behaviors

Abstract Background Cannabis usage is increasing with its widespread legalization. Cannabis use by mothers during lactation transfers active cannabinoids to the developing offspring during this critical period and alters postnatal neurodevelopment. A key neurodevelopmental landmark is the excitatory to inhibitory GABA switch caused by reciprocal changes in expression ratios of the K+/Cl- transporters KCC2 and NKCC1. Methods Rat dams were treated with THC or a synthetic cannabinoid during the first 10 days of postnatal development and experiments were then conducted in the offspring exposed to these drugs via lactation. The network influence of GABA transmission was analyzed using cell-attached recordings. KCC2 and NKCC1 levels were determined using Western blot and qPCR analyses. USV and homing behavioral experiments were carried out at relevant time-points. Results Treating rat dams with cannabinoids during early lactation retards transcriptional upregulation and expression of KCC2, thereby delaying the GABA switch in pups of both sexes. This perturbed trajectory was corrected by the NKCC1 antagonist bumetanide and accompanied by alterations in ultrasonic vocalization without changes in homing behavior. Neurobehavioral deficits were prevented by CB1R antagonism during maternal exposure, showing that CB1R underlie the cannabinoid-induced alterations. Conclusions These results reveal how perinatal cannabinoid exposure retards an early milestone of development, delaying the trajectory of GABA’s polarity transition and altering early-life communication.