Microglial cannabinoid receptor type 1 mediates social memory deficits in mice produced by adolescent THC exposure and 16p11.2 duplication | Nature Communications Download PDF ### Subjects - Cellular neuroscience - Development of the nervous system ## Abstract Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. However, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, is not fully understood. Here, we report that in mice, adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in a model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings suggest the microglial Cnr1 may contribute to

hippocampal neurons caused a delayed increase in [Ca 2+ ] i that reached a maximum at 90 min (Fig. 4 A ). Treatment of neurons with 2 μ m THC also increased [Ca 2+ ] i but with slower kinetics (data not shown). When cells were treated with THC without extracellular Ca 2+ and in the presence of EGTA, there was no significant increase in [Ca 2+ ] i (Fig. 4 A ). Addition of extracellular Ca 2+ at the end of this incubation led to an instantaneous rise in [Ca 2+ ] i , suggesting that a plasma membrane channel is activated by THC. Lanthanum, a potent blocker of Ca 2+ channels, completely inhibited this rise in [Ca 2+ ] i (Fig. 4 B ). THC-induced Ca 2+ increases were also inhibited by the cannabinoid receptor antagonist SR141716A (Fig. 4 C ). Because stimulation of CB1 receptors increased [Ca 2+ ] i , we examined the effect of chelating Ca 2+ on THC neurotoxicity. Chelation of extracellular Ca 2+ with EGTA did not rescue hippocampal neurons from THC toxicity (Fig. 5 ). This suggests that THC neurotoxicity is not dependent on increases in intracellular Ca 2+ , because THC-stimulated increases in [Ca 2+ ] i required extracellular Ca 2+ . This distinguishes THC neurotoxicity from other forms of toxicity that are triggered by increased [Ca 2+ ] i . Fig. 4. Open in a new tab THC induces a delayed increase in intracellular Ca 2+ that is dependent on extracellular Ca 2+ . [Ca 2+ ] i of THC-treated primary hippocampal neurons was monitored by fura-2 fluorescent imaging. The calibrated [Ca 2+ ] i (n m ) was plotted against time (minutes). A , THC was added to neurons in the presence of 1.5 m m CaCl 2 (THC + Ca 2+ ) at the indicated time ( arrow ). No increase in intracellular Ca 2+ was seen when the ethanol carrier (0.01%) was added alone (data not shown) or when THC was added to cells incubated without Ca 2+ in the presence of 5 m m EGTA (THC − Ca 2+ ). Four m m LaCl 3 ( B ) or 5 μ m SR141716A ( C ) blocked increases in [Ca 2+ ] i caused by 10 μ m THC. Fig. 5. Open in a new tab T