Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice.
Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice.
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半胱胺治疗可改善杂合 reeler 小鼠中 GAD67 表达和空间记忆的变化。
DOI：
10.1017/s1461145711001180
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Pillai,Anilkumar
中科院分区：
文献类型：
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作者：
Kutiyanawalla,Ammar;Promsote,Wanwisa;Terry,Alvin;Pillai,Anilkumar
已知脑源性神经营养因子（BDNF）通过其受体TrkB信号传导调节GABA能功能和神经元中的谷氨酸脱羧酶（GAD）67表达。BDNF信号传导的改变与精神分裂症的病理生理学有关，因此，它们是潜在的治疗靶点。有趣的是，杂合子reeler小鼠（HRM）在额叶皮层和海马中GAD 67表达降低，并且它们表现出许多类似于精神分裂症的行为和神经化学异常。在这项研究中，我们评估了半胱胺，一种神经保护化合物，以改善GAD 67表达和认知功能的缺陷在HRM的潜力。我们发现，半胱胺给药（150 mg/kg.d，通过饮用水）30 d显著改善了HRM额叶皮质和海马中GAD 67、成熟BDNF和全长TrkB蛋白水平的降低。在半胱胺处理后，还观察到HRM的额叶皮质和海马中的截短BDNF以及额叶皮质中的截短TrkB的增加水平的显著衰减。在行为学研究中，HRM在Y-迷宫空间识别记忆任务中受损，但在自发交替任务或感觉运动前脉冲抑制（PPI）程序中未受损。半胱胺改善HRM中Y-迷宫空间识别至野生型对照的水平，并且其改善野生型和HRM两者中的PPI。最后，TrkB缺陷的小鼠在GAD 67表达中显示出对半胱胺的响应降低，表明TrkB信号传导在半胱胺对GAD 67的调节中起重要作用。
Brain-derived neurotrophic factor (BDNF) signalling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signalling have been implicated in the pathophysiology of schizophrenia and as a result, they are a potential therapeutic target. Interestingly, heterozygous reeler mice (HRM) have decreased GAD67 expression in the frontal cortex and hippocampus and they exhibit many behavioural and neurochemical abnormalities similar to schizophrenia. In this study, we evaluated the potential of cysteamine, a neuroprotective compound to improve the deficits in GAD67 expression and cognitive function in HRM. We found that cysteamine administration (150 mg/kg.d, through drinking water) for 30 d significantly ameliorated the decreases in GAD67, mature BDNF and full-length TrkB protein levels found in frontal cortex and hippocampus of HRM. A significant attenuation of the increased levels of truncated BDNF in frontal cortex and hippocampus, as well as truncated TrkB in frontal cortex of HRM was also observed following cysteamine treatment. In behavioural studies, HRM were impaired in a Y-maze spatial recognition memory task, but not in a spontaneous alternation task or a sensorimotor, prepulse inhibition (PPI) procedure. Cysteamine improved Y-maze spatial recognition in HRM to the level of wide-type controls and it improved PPI in both wild-type and HRM. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in GAD67 expression suggesting that TrkB signalling plays an important role in GAD67 regulation by cysteamine.