Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration

• DOI: 10.1016/j.neuint.2018.07.009
• Publication Date: 2018-07-24T19:31:50Z
• Authors: Yun Zhou; Roni Dhaher; Maxime Parent; Qiu-Xiang Hu; Bjørnar Hassel; Siu-Pok Yee; Fahmeed Hyder; Shaun E. Gruenbaum; Tore Eid; Niels Christian D...
• Keywords: Cerebral Cortex; Male; 570; 0303 health sciences; Epilepsy; Amino Acid Transport System X-AG; Glutamic Acid; Hippocampus; Disease Models, Animal; Mice; 03 medical and health sciences; Receptors, Glutamate; Glutamate-Ammonia Ligase; Astrocytes; 616; Glial Fibrillary Acidic Protein; Animals; Female; Neuroglia

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.