St8sia2 deficiency plus juvenile cannabis exposure in mice synergistically affect higher cognition in adulthood

• NCAM and its functionally linked polysialyltransferases are crucial for synaptic plasticity.
• Genetically reduced polySia expression (St8sia2−/−) as well as Δ9-THC affect NCAM polysialylation.
• Juvenile exposure to Δ9-THC acts as environmental ‘second hit’ on cognition of St8sia2−/− mice.
• This double-hit reduces hippocampal polysialic acid-free NCAM-180 and increases dentate polysialic acid.
• St8sia2−/− plus Δ9-THC deliver a mechanistically plausible example of a genes × environment effect.

The neural cell adhesion molecule (NCAM) and its functionally linked polysialyltransferases, ST8SIA2 and ST8SIA4, are crucial for synaptic plasticity. Variations in encoding genes have been associated with mental illness. Since cannabinoids can alter NCAM polysialylation, we hypothesized that delta-9-tetrahydrocannabinol (Δ9-THC) might act as environmental ‘second hit’ regarding cognition of St8sia2−/− mice. These mice show per se minor behavioral abnormalities, consisting of reduced anxiety and mild cognitive deficits. Chronic Δ9-THC treatment of juvenile male wildtype mice (St8sia2+/+) (7 mg/kg every other day over 3 weeks) did not appreciably affect cognition. St8sia2−/− mice, however, displayed a synergistic negative consequence of Δ9-THC on learning/memory, accompanied by polysialic acid-free NCAM-180 reduction in hippocampus and polysialic acid increase in dentate outer molecular layer. These synergistic effects became obvious only months after the last Δ9-THC. We conclude that juvenile cannabis exposure may cause delayed but lasting damage on cognition in subjects genetically predisposed to altered NCAM polysialylation.