Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852-9411, USA.
Neurobiol Dis. 2010 Dec;40(3):608-21. doi: 10.1016/j.nbd.2010.08.005. Epub 2010 Aug 8.
Glutamatergic dysfunction is strongly implicated in schizophrenia and mood disorders. GluA1 knockout (KO) mice display schizophrenia- and depression-related abnormalities. Here, we asked whether GluA1 KO show mania-related abnormalities. KO were tested for behavior in approach/avoid conflict tests, responses to repeated forced swim exposure, and locomotor responses under stress and after psychostimulant treatment. The effects of rapid dopamine depletion and treatment with lithium or a GSK-3β inhibitor (SB216763) on KO locomotor hyperactivity were tested. Results showed that KO exhibited novelty- and stress-induced locomotor hyperactivity, reduced forced swim immobility and alterations in approach/avoid conflict tests. Psychostimulant treatment and dopamine depletion exacerbated KO locomotor hyperactivity. Lithium, but not SB216763, treatment normalized KO anxiety-related behavior and partially reversed hyperlocomotor behavior, and also reversed elevated prefrontal cortex levels of phospho-MARCKS and phospho-neuromodulin. Collectively, these findings demonstrate mania-related abnormalities in GluA1 KO and, combined with previous findings, suggest this mutant may provide a novel model of features of schizoaffective disorder.
谷氨酸能功能障碍在精神分裂症和心境障碍中起着重要作用。GluA1 敲除 (KO) 小鼠表现出与精神分裂症和抑郁症相关的异常。在这里，我们想知道 GluA1 KO 是否表现出与躁狂症相关的异常。对 KO 进行了接近/回避冲突测试、反复强迫游泳暴露后的反应以及应激和精神兴奋剂治疗后的运动反应测试。测试了快速多巴胺耗竭和锂或 GSK-3β 抑制剂 (SB216763) 治疗对 KO 运动过度兴奋的影响。结果表明，KO 表现出新奇和应激诱导的运动过度兴奋、强迫游泳不动性降低以及接近/回避冲突测试中的改变。精神兴奋剂治疗和多巴胺耗竭加剧了 KO 的运动过度兴奋。锂，但不是 SB216763，治疗使 KO 的焦虑相关行为正常化，并部分逆转了过度运动行为，还逆转了前额叶皮层中磷酸化-MARCKS 和磷酸化神经调节蛋白水平的升高。总之，这些发现表明 GluA1 KO 存在与躁狂症相关的异常，并且结合以前的发现，表明该突变体可能提供精神分裂情感障碍特征的新型模型。
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