title: Persistent reduction of hippocampal glutamine synthetase expression after status epilepticus in immature rats.
abstract: Mesiotemporal sclerosis (MTS), the most frequent form of drug-resistant temporal lobe epilepsy, often develops after an initial precipitating injury affecting the immature brain. To analyse early processes in epileptogenesis we used the juvenile pilocarpine model to study status epilepticus (SE)-induced changes in expression of key components in the glutamate-glutamine cycle, known to be affected in MTS patients. SE was induced by Li(+) /pilocarpine injection in 21-day-old rats. At 2-19 weeks after SE hippocampal protein expression was analysed by immunohistochemistry and neuron damage by FluoroJade staining. Spontaneous seizures occurred in at least 44% of animals 15-18 weeks after SE. As expected in this model, we did not observe loss of principal hippocampal neurons. Neuron damage was most pronounced in the hilus, where we also detected progressive loss of parvalbumin-positive GABAergic interneurons. Hilar neuron loss (or end-folium sclerosis), a common feature in patients with MTS, was accompanied by a progressively decreased glutamine synthetase (GS)-immunoreactivity from 2 (-15%) to 19 weeks (-33.5%) after SE. Immunoreactivity for excitatory amino-acid transporters, vesicular glutamate transporter 1 and glial fibrillary acidic protein was unaffected. Our data show that SE elicited in 21-day-old rats induces a progressive reduction in hilar GS expression without affecting other key components of the glutamate-glutamine cycle. Reduced expression of glial enzyme GS was first detected 2 weeks after SE, and thus clearly before spontaneous recurrent seizures occurred. These results support the hypothesis that reduced GS expression is an early event in the development of hippocampal sclerosis in MTS patients and emphasize the importance of astrocytes in early epileptogenesis.
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584CG, Utrecht, The Netherlands; Division of Surgical Specialties, Department of Anatomy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: W Saskia
authors.initials: WS
authors.lastname: van der Hel
authors.forename: Ellen V S
authors.initials: EV
authors.lastname: Hessel
authors.forename: Ineke W M
authors.initials: IW
authors.lastname: Bos
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Mulder
authors.forename: Suzanne A M W
authors.initials: SA
authors.lastname: Verlinde
authors.forename: Pieter
authors.initials: P
authors.lastname: van Eijsden
authors.forename: Pierre N E
authors.initials: PN
authors.lastname: de Graan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology* / Q000254:growth & development* / Q000473:pathology; D007150:Immunohistochemistry; D008094:Lithium; D008297:Male; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010320:Parvalbumins / Q000378:metabolism; D010862:Pilocarpine; D017208:Rats, Wistar; D012640:Seizures / Q000201:enzymology / Q000473:pathology; D013226:Status Epilepticus / Q000201:enzymology* / Q000473:pathology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D010320:Parvalbumins; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D010862:Pilocarpine; D005680:gamma-Aminobutyric Acid; D008094:Lithium; D005974:Glutamate-Ammonia Ligase
keywords: GABA; epileptogenesis; glutamate-glutamine cycle; juvenile pilocarpine model; mTLE