CB1 and CB2 receptors differentially modulate the cognitive impact of maternal immune activation and perinatal cannabinoid exposure

Abstract

Maternal immune activation (MIA) commonly arises in response to an infection during pregnancy. MIA elevates cytokine levels, triggering an inflammatory cascade, which may be detrimental to the developing nervous system. Similarly, cannabis use and exposure of the fetus to cannabinoids during pregnancy (PCE) may elicit neuroinflammation and lead to detrimental behavioral outcomes. This is particularly concerning as there has been a notable rise in cannabis use during pregnancy. This study endeavors to examine the interaction between MIA and PCE and elucidate the role of CB1 and CB2 receptors in MIA and PCE outcomes. To this end, we compared the impact of MIA, PCE and MIA+PCE in wildtype, CB1, and CB2 cannabinoid receptor knockout mice of both sexes. PCE was modeled by daily 3 mg/kg THC administration from gestational day 5 (GD5) to postnatal day 10. MIA was modeled by intravenous Poly (I:C) injection at GD16.5. Subsequently, we assessed emotional and cognitive behaviors of adult offspring. Adult male offspring of dams exposed to PCE or MIA were impaired in novel object recognition and the delayed alternation working memory tasks. Interestingly, these behavioral impairments were absent when MIA and PCE were combined. Cannabinoid receptor knockout studies found that CB1 receptors mediated behavioral deficits after PCE. In contrast CB2 receptors were necessary for full expression of MIA-induced behavioral impairments. Although females showed more modest behavioral changes after MIA or PCE, CB1 receptors were required for the PCE deficit and CB2 receptors were required for the MIA deficit also in females. Notably, lack of CB2 receptors in males prevented the “protection” following combined MIA + PCE, while CB1 knockout mice remained protected. Taken together, these results suggest a complex interplay between PCE, MIA and CB1 and CB2 cannabinoid receptors.