Up-Regulation of Metabotropic Glutamate Receptor 5 Immunoreactivity in the Hippocampus of Patients with Intractable Temporal Lobe Epilepsy.
Abstract number :
2.042
Submission category :
Year :
2001
Submission ID :
193
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
R.G.E. Notenboom, PhD, Pharmacology and Anatomy, Rudolf Magnus Institute for Neurosciences, Utrecht, Netherlands; G.H. Jansen, MD, Pathology, University Medical Center Utrecht, Utrecht, Netherlands; C.WM. van Veelen, MD,PhD, Neurosurgery, University Medic
RATIONALE: Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors, which can modulate the intracellular responses to synaptically released glutamate in various ways. To date, at least eight mGluRs have been cloned, including their human equivalents. Based on sequence homology, pharmacological properties and signal transduction pathways mGluRs are divided into three groups. Group I mGluRs, which are positively linked to phosphoinositide hydrolysis, and group II/III mGluRs, which are negatively coupled to adenylyl cyclase. Group I mGluRs (mGluR1 and 5) are predominantly located postsynaptically and increase neuronal excitability, presumably by release of Ca2+ from intracellular stores and potentiation of ionotropic glutamate receptors. Because of these properties, group I mGluRs may contribute to neuronal injury, and promote neuronal hyperexcitability in epileptogenic foci. This study determined hippocampal mGluR1 and mGluR5 immunoreactivity (IR) in surgical resection tissue from pharmaco-resistant temporal lobe epilepsy (TLE) patients.
METHODS: The IR pattern of tissue samples from TLE patients with (n = 6) and without (n = 6) hippocampal sclerosis (HS) was compared to that of autopsy controls (n = 6) without neuropathology. Comparison of non-HS (Wyler grade 0) and HS (Wyler grade 4) patients revealed no significant differences with respect to the age at the time of surgery (non-HS: 27.7[plusminus]9.9 years vs. HS: 32.3[plusminus]12.0 years), the age at seizure onset (non-HS: 11.3[plusminus]8.3 years vs. HS: 16.9[plusminus]11.6 years) and the duration of epilepsy (non-HS: 16.3[plusminus]8.0 years vs. HS: 15.4[plusminus]7.9 years). The mean age of the autopsy controls was 30.7[plusminus]4.7 years. IR was detected with commercial receptor subtype specific antisera on paraffin-embedded tissue sections.
RESULTS: We found a marked increase of mGluR5 IR in the cell bodies and apical dendrites of principal hippocampal neurons and in the dentate gyrus molecular layer of TLE patients, as compared to autopsy controls, which was most pronounced in HS patients. In TLE patients, increased mGluR5 IR was also observed in (reactive) glial cells. In contrast, mGluR1 IR was found in neuronal cell bodies and no differences were observed in hippocampal mGluR1 IR between TLE patients and autopsy controls.
CONCLUSIONS: These data demonstrate a striking up-regulation of mGluR5 IR associated with TLE and support a prominent role of this receptor in epilepsy and epilepsy-related neurotoxicity.
Support: NEF grant 98-16 from the Epilepsy Fund of the Netherlands