GSK-3参与代谢型谷氨酸受体2激动剂治疗精神分裂症认知障碍的作用及其机制

In schizophrenia (SZ), cognitive impairment (CI) is considered as the most complicated and refractory symptom. Currently, NMDAR hypo-function in the prefrontal cortex (PFC) is strongly implicated in the pathological mechanisms of CI in SZ. There is lack of safely effective antipsychotics for CI clinical treatment at present. Our study showed that administration with mGluR2 agonist LY39 at juvenile period successfully ameliorated the CI induced by MAM in adulthood. Meanwhile, LY39 significantly enhanced postsynaptic NMDAR expression and function in PFC. LY39 inhibited GSK-3β activity through upregulation of phosphorylation of S9. Does LY39 exert its treatment effects for CI through GSK-3β inhibition? Our previous study in other SZ models demonstrated that GSK-3β mediated NMDAR downregulation and CI. Together with the knowledge that GSK-3α and GSK-3β share similar substrates and are regulated in similar way of N-terminal inhibitory phosphorylation, we propose that LY39 rescues synaptic NMDAR expression and function in PFC and in turn ameliorate CI in schizophrenia by upregulation of inhibitory phosphorylation of GSK-3α/β S21/S9. Our study will provide important scientific evidences for mechanisms of CI treatment with mGluR2 agonists and CI treatment development in SZ.

精神分裂症（精分）的认知障碍（CI）是最复杂、难治的症状，目前认为前额叶皮层（PFC）突触性NMDAR功能低下是其主要发病机制，但临床上尚无安全有效的CI治疗药物。我们发现青年期甲基氧化偶氮甲醇（MAM）精分模型大鼠给予mGluR2激动剂LY395756（LY39）可有效改善成年期CI，同时显著增强PFC突触性NMDAR表达及功能；LY39上调GSK-3β S9抑制性磷酸化从而抑制其激酶活性。那么LY39是否通过抑制GSK-3β发挥CI治疗作用？我们以往在其它精分相关模型证明GSK-3β介导突触性NMDAR表达下调及CI发生；结合已知GSK-3α与β相似的调控机制和底物，我们提出科学假说：LY39通过上调GSK-3α/β S21/S9抑制性磷酸化从而恢复PFC突触性NMDAR表达、改善CI。本项目拟验证该假说，为阐明mGluR2激动剂治疗CI的机制、开发精分CI治疗药物提供科学依据。

简介:在精神分裂症的发病机制中发现突触性NR2B明显减少。最近的研究表明，代谢型谷氨酸受体2激动剂/3拮抗剂LY395756可以有效恢复成年MAM精神分裂症模型小鼠的NR2B水平，提高其认知能力。然而，具体的潜在机制尚不清楚。.材料和方法:采用MAM精神分裂症小鼠模型。采用qPCR和western blotting检测不同处理条件下NMDAR突触膜蛋白水平。用染色质免疫沉淀(ChIP)法检测CREB与NR2B启动子的相互作用及LY395756介导NR2B的信号通路。.结果:发现CREB能与NR2B启动子miR-135a-2直接结合。同时LY395756激活AKT的磷酸化，磷酸化的AKT随后诱导CREB磷酸化，激活的CREB促进NR2B的表达。后续实验表明，蛋白磷酸酶1（PP1）可诱导CREB去磷酸化从而抑制NR2B水平。综上所述，该研究发现LY395756通过AKT/CREB信号通路促进NR2B表达作用，对将来精神分裂症认知障碍的改善至关重要。.结论:我们的研究发现了LY395756能通过AKT/CREB信号增加NR2B表达，进一步的机制表明CREB可与NR2B的启动子直接结合。这一研究结果有望成为精神分裂症认知障碍临床治疗的潜在方向。

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