Inhibition of glutamine synthetase in the central nucleus of the amygdala induces anhedonic behavior and recurrent seizures in a rat model of mesial temporal lobe epilepsy.
Inhibition of glutamine synthetase in the central nucleus of the amygdala induces anhedonic behavior and recurrent seizures in a rat model of mesial temporal lobe epilepsy.
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DOI：
10.1016/j.yebeh.2015.07.015
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Dhaher R
中科院分区：
文献类型：
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作者：
Gruenbaum SE;Wang H;Zaveri HP;Tang AB;Lee TS;Eid T;Dhaher R
内侧颞叶癫痫(MTLE)患者抑郁和自杀的发生率增加；然而，其潜在的机制仍不清楚。快感缺乏是抑郁症的核心症状，预示着自杀，在MTLE患者中很常见。谷氨酰胺合成酶是一种将谷氨酸和氨代谢为谷氨酰胺的星形细胞酶，在癫痫和抑郁症患者以及自杀受害者的杏仁核中，谷氨酰胺合成酶会减少。在这里，我们试图通过测试杏仁中央核(CEA)谷氨酰胺合成酶缺乏导致癫痫和共病快感缺失的假说来发展一种新的MTLE快感缺失模型。将19只雄性SD大鼠植入渗透泵，向右侧CEA注入谷氨酰胺合成酶抑制剂蛋氨酸亚硫胺[MSO(n=12)]或磷酸盐缓冲盐水[PBS(n=7)]。在MSO注射开始后21d，用视频-颅内脑电(EEG)记录监测癫痫活动。21天后，对蔗糖偏好进行评估，这是快感缺失的一种衡量标准。与注射PBS的大鼠相比，注射蛋氨酸亚磺胺的大鼠在监测期间表现出反复的癫痫发作，并且随着时间的推移表现出对蔗糖的偏好降低(p<；0.01)。PBS处理组和MSO处理组之间的用水量没有差异。在MSO处理的大鼠中，CEA中的神经元丢失，但杏仁内侧核、杏仁外侧核、杏仁基底外侧核或齿状回的门不丢失。结果提示，CEA中谷氨酰胺合成酶活性降低可能是TLE快感障碍和癫痫发作的共同原因。我们建议MSO CEA模型可用于机制研究，从而开发和测试预防TLE患者癫痫发作、抑郁和自杀的新药。
The prevalence of depression and suicide is increased in patients with mesial temporal lobe epilepsy (MTLE); however, the underlying mechanism remains unknown. Anhedonia, a core symptom of depression that is predictive of suicide, is common in patients with MTLE. Glutamine synthetase, an astrocytic enzyme that metabolizes glutamate and ammonia to glutamine, is reduced in the amygdala in patients with epilepsy and depression and in suicide victims. Here, we sought to develop a novel model of anhedonia in MTLE by testing the hypothesis that deficiency in glutamine synthetase in the central nucleus of the amygdala (CeA) leads to epilepsy and comorbid anhedonia. Nineteen male Sprague–Dawley rats were implanted with an osmotic pump infusing either the glutamine synthetase inhibitor methionine sulfoximine [MSO (n = 12)] or phosphate buffered saline [PBS (n = 7)] into the right CeA. Seizure activity was monitored by video-intracranial electroencephalogram (EEG) recordings for 21 days after the onset of MSO infusion. Sucrose preference, a measure of anhedonia, was assessed after 21 days. Methionine sulfoximine-infused rats exhibited recurrent seizures during the monitoring period and showed decreased sucrose preference over days when compared with PBS-infused rats (p < 0.01). Water consumption did not differ between the PBS-treated group and the MSO-treated group. Neurons were lost in the CeA, but not the medial amygdala, lateral amygdala, basolateral amygdala, or the hilus of the dentate gyrus, in the MSO-treated rats. The results suggest that decreased glutamine synthetase activity in the CeA is a possible common cause of anhedonia and seizures in TLE. We propose that the MSO CeA model can be used for mechanistic studies that will lead to the development and testing of novel drugs to prevent seizures, depression, and suicide in patients with TLE.