Abstract：
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212-2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.
摘要：
细胞周期蛋白依赖性激酶5（CDK5）是一种丝氨酸/苏氨酸激酶，已成为复杂认知过程中神经传递的关键调节剂。它的表达在接受治疗的精神分裂症患者中发生了改变，和大麻素调节啮齿动物大脑中的CDK5水平。然而,这种激酶的作用，在首发精神病（FEP）患者中，其与大麻使用的相互作用仍然未知。因此，我们研究了CDK5及其信号伴侣的表达变化，曾使用大麻（FEP/c）和未使用（FEP/nc）的FEP患者的嗅觉神经上皮（ON）细胞中的突触后密度蛋白95（PSD95），在精神病的双重打击小鼠模型中。在这个模型中,青春期小鼠暴露于大麻素受体1激动剂（CB1R）WIN-55,212-2（WIN：1mg/kg）21天，和N-甲基-d-天冬氨酸受体（NMDAR）阻断剂苯环利定（PCP：10mg/kg），持续10天。FEP/c显示较少的社会功能缺陷，低于FEP/NC的CDK5和PSD95水平。这些变化与社交技能相关，但不是认知缺陷。始终如一，FEP/nc患者的ON细胞暴露于WIN体外降低了CDK5水平。在小鼠中获得收敛结果，PCP本身会导致更多的社交能力缺陷，与暴露于PCP-WIN相比，前额叶皮质和海马中的PSD95/CDK5改变。此外,PCP治疗的小鼠中，roscovitine对CDK5活性的中枢阻断恢复了社交能力障碍和PSD95水平。我们提供了转化证据，表明CDK5增加可能是与社会缺陷相关的精神病的早期指标，并且这种生物标志物是通过先前使用大麻来调节的。
