Glutamate-ammonia ligase (glutamine synthetase; Glul) is enriched in astrocytes and serves as the primary enzyme for ammonia detoxification and glutamate inactivation in the brain. Loss of astroglial Glul is reported in hippocampi of epileptic patients, but the mechanism by which Glul deficiency might cause disease remains elusive. Here we created a novel mouse model by selectively deleting Glul in the hippocampus and neocortex. The Glul deficient mice were born without any apparent malformations and behaved unremarkably until postnatal week three. There were reductions in tissue levels of aspartate, glutamate, glutamine and GABA and in mRNA encoding glutamate receptor subunits GRIA1 and GRIN2A as well as in the glutamate transporter proteins EAAT1 and EAAT2. Adult Glul-deficient mice developed progressive neurodegeneration and spontaneous seizures which increased in frequency with age. Importantly, progressive astrogliosis occurred before neurodegeneration and was first noted in astrocytes along cerebral blood vessels. The responses to CO2-provocation were attenuated at four weeks of age and dilated microvessels were observed histologically in sclerotic areas of cKO. Thus, the abnormal glutamate metabolism observed in this model appeared to cause epilepsy by first inducing gliopathy and disrupting the neurovascular coupling.

中文翻译：

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小鼠大脑皮层中谷氨酰胺合成酶的选择性缺失会引起癫痫和神经变性之前的神经胶质功能障碍和血管损伤。

谷氨酸氨连接酶（谷氨酰胺合成酶； Glu1）富含星形胶质细胞，并充当大脑中氨解毒和谷氨酸失活的主要酶。据报道，癫痫患者海马中星形胶质细胞丢失了Glul，但是缺乏Glul可能导致疾病的机制尚不清楚。在这里，我们通过选择性地删除海马和新皮层中的Glul，创建了一个新颖的小鼠模型。Glul缺陷型小鼠出生时没有任何明显的畸形，直到出生后第三周表现不明显。天冬氨酸，谷氨酸，谷氨酰胺和GABA的组织水平以及编码谷氨酸受体亚基GRIA1和GRIN2A的mRNA以及谷氨酸转运蛋白EAAT1和EAAT2都有降低。成年的Glul缺陷小鼠发展为进行性神经变性和自发性癫痫，其频率随着年龄的增长而增加。重要的是，进行性星形胶质增生发生在神经变性之前，并首先在脑血管的星形胶质细胞中发现。对CO2激发的反应在4周龄时减弱，并且在cKO的硬化区域中在组织学上观察到扩张的微血管。因此，在该模型中观察到的异常谷氨酸代谢似乎通过首先诱发神经胶质病和破坏神经血管偶联而引起癫痫病。对CO2激发的反应在4周龄时减弱，并且在cKO的硬化区域中在组织学上观察到扩张的微血管。因此，在该模型中观察到的异常谷氨酸代谢似乎通过首先诱发神经胶质病和破坏神经血管偶联而引起癫痫病。对CO2激发的反应在4周龄时减弱，并且在cKO的硬化区域中在组织学上观察到扩张的微血管。因此，在该模型中观察到的异常谷氨酸代谢似乎通过首先诱发神经胶质病和破坏神经血管偶联而引起癫痫病。