星形胶质增生
谷氨酸受体
神经退行性变
谷氨酰胺
谷氨酰胺合成酶
癫痫
星形胶质细胞
谷氨酰胺酶
大脑皮层
内分泌学
海马体
内科学
化学
神经科学
生物
医学
中枢神经系统
生物化学
受体
疾病
氨基酸
作者
Yun Zhou,Roni Dhaher,Maxime Parent,Qiu Xiang Hu,Bjørnar Hassel,Siu‐Pok Yee,Fahmeed Hyder,Shaun E. Gruenbaum,Tore Eid,Niels Christian Danbolt
标识
DOI:10.1016/j.neuint.2018.07.009
摘要
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.
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