RESUMO
Psychotic disorders entail intricate conditions marked by disruptions in cognition, perception, emotions, and social behavior. Notably, psychotic patients who use cannabis tend to show less severe deficits in social behaviors, such as the misinterpretation of social cues and the inability to interact with others. However, the biological underpinnings of this epidemiological interaction remain unclear. Here, we used the NMDA receptor blocker phencyclidine (PCP) to induce psychotic-like states and to study the impact of adolescent cannabinoid exposure on social behavior deficits and synaptic transmission changes in hippocampal area CA2, a region known to be active during social interactions. In particular, adolescent mice underwent 7 days of subchronic treatment with the synthetic cannabinoid, WIN 55, 212-2 (WIN) followed by one injection of PCP. Using behavioral, biochemical, and electrophysiological approaches, we showed that PCP persistently reduced sociability, decreased GAD67 expression in the hippocampus, and induced GABAergic deficits in proximal inputs from CA3 and distal inputs from the entorhinal cortex (EC) to CA2. Notably, WIN exposure during adolescence specifically restores adult sociability deficits, the expression changes in GAD67, and the GABAergic impairments in the EC-CA2 circuit, but not in the CA3-CA2 circuit. Using a chemogenetic approach to target EC-CA2 projections, we demonstrated the involvement of this specific circuit on sociability deficits. Indeed, enhancing EC-CA2 transmission was sufficient to induce sociability deficits in vehicle-treated mice, but not in animals treated with WIN during adolescence, suggesting a mechanism by which adolescent cannabinoid exposure rescues sociability deficits caused by enhanced EC-CA2 activity in adult mice.
RESUMO
Alzheimer's disease (AD) is the most common type of dementia and neurodegeneration. The actual cause of AD progression is still unknown and no curative treatment is available. Recently, findings in human samples and animal models pointed to the endocannabinoid system (ECS) as a promising therapeutic approach against AD. However, the specific mechanisms by which cannabinoid drugs induce potential beneficial effects are still undefined. For this reason, it is required a full characterization of the ECS at different time points of AD progression considering important factors such as sex or the analysis of different brain regions to improve future cannabinoid-dependent therapies in AD. Thus, the main aim of the present study is to expand our knowledge of the status of the ECS in a presymptomatic period (3 months of age) using the AD mouse model APP/PS1 mice. First, we evaluated different behavioral domains including anxiety, cognitive functions, and social interactions in male and female APP/PS1 mice at 4 months of age. Although a mild working memory impairment was observed in male APP/PS1 mice, in most of the behaviors assessed we found no differences between genotypes. At 3 months of age, we performed a characterization of the ECS in different brain regions of the APP/PS1 mice considering the sex variable. We assessed the expression of the ECS components by quantitative Real-Time Polymerase Chain Reaction in the hippocampus, prefrontal cortex, hypothalamus, olfactory bulb, and cerebellum. Interestingly, gene expression levels of the type-1 and type-2 cannabinoid receptors and the anabolic and catabolic enzymes, differed depending on the brain region and the sex analyzed. For example, CB1R expression levels decreased in both hippocampus and prefrontal cortex of male APP/PS1 mice but increased in female mice. In contrast, CB2R expression was decreased in females, whereas males tended to have higher levels. Overall, our data indicated that the ECS is already altered in APP/PS1 mice at the presymptomatic stage, suggesting that it could be an early event contributing to the pathophysiology of AD or being a potential predictive biomarker.
