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Reduced glutamine synthetase in hippocampal areas with neuron loss in temporal lobe epilepsy

From the Departments of Pharmacology and Anatomy (W.S. van der Hel and I.W.M. Bos, and Drs. Notenboom and de Graan) and Neurosurgery (Drs. van Rijen and van Veelen), Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.

Address correspondence and reprint requests to Dr. P.N.E. de Graan, Rudolf Magnus Institute of Neuroscience, Department of Pharmacology & Anatomy, University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands; e-mail: p.n.e.degraan{at}med.uu.nl

Background: Increased levels of glutamate have been reported in the epileptogenic hippocampus of patients with temporal lobe epilepsy (TLE). This sustained increase, which may contribute to the initiation and propagation of seizure activity, indicates impaired clearance of glutamate released by neurons. Glutamate is predominantly cleared by glial cells through the excitatory amino acid transporter 2 (EAAT2) and its subsequent conversion to glutamine by the glial enzyme glutamine synthetase (GS).

Methods: The authors examined the hippocampal distribution of GS, EAAT2, and glial fibrillary acidic protein (GFAP) by immunohistochemistry in TLE patients with (HS group) and without hippocampal sclerosis (non-HS group), and in autopsy controls. In hippocampal homogenates the authors measured relative protein amounts by immunoblotting and GS enzyme activity.

Results: In the autopsy control and non-HS group GS immunoreactivity (IR) was predominantly found in glia in the neuropil of the subiculum, of the pyramidal cell layer of all CA fields, and in the supragranular layer of the dentate gyrus. In the HS group, GS and EAAT2 IR were markedly reduced in subfields showing neuron loss (CA1 and CA4), whereas GFAP IR was increased. The reduction in GS IR in the HS group was confirmed by immunoblotting and paralleled by decreased GS enzyme activity.

Conclusions: Glial glutamine synthetase is downregulated in the hippocampal sclerosis (HS) hippocampus of temporal lobe epilepsy (TLE) patients in areas with severe neuron loss. This downregulation appears to be pathology-related, rather than seizure-related, and may be part of the mechanism underlying impaired glutamate clearance found in the hippocampus of TLE patients with HS.

Supported by The Epilepsy Fund of the Netherlands (grant 98–16 and 01–05) and by the Foundation Focal Epilepsies of Childhood.

Received March 9, 2004. Accepted in final form October 8, 2004.

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