精神疾病需要复杂的疾病,以认知中断为特征,感知,情感,和社会行为。值得注意的是,使用大麻的精神病患者往往表现出不那么严重的社会行为缺陷,例如对社会线索的误解和无法与他人互动。然而,这种流行病学相互作用的生物学基础仍不清楚.这里,我们使用NMDA受体阻滞剂苯环利定(PCP)诱导精神病样状态,并研究青少年大麻素暴露对海马CA2区社会行为缺陷和突触传递变化的影响,该区域已知在社会互动过程中活跃.特别是,青春期小鼠接受合成大麻素的亚慢性治疗7天,WIN55,212-2(WIN),然后注射一次PCP。使用行为,生物化学,和电生理学方法,我们发现PCP持续降低社交能力,海马中GAD67表达减少,并在CA3的近端输入和内嗅皮层(EC)到CA2的远端输入中诱导GABA能缺陷。值得注意的是,青春期的胜利暴露特别能恢复成人的社交能力缺陷,GAD67的表达变化和EC-CA2回路中的GABA能损伤,但不在CA3-CA2电路中。使用化学遗传学方法来靶向EC-CA2预测,我们证明了这个特定电路对社交能力缺陷的参与。的确,增强EC-CA2传播足以诱导载体治疗小鼠的社交能力缺陷,但在青春期接受WIN治疗的动物中却没有,提示青少年大麻素暴露可挽救成年小鼠EC-CA2活性增强引起的社交能力缺陷的机制。
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.