|PI of the laboratory: Alexandre Croquelois
Tél: 021 314 14 76
Direct supervisor (assistant): Michel Kielar
Tél: 021 692 51 34,
Department: Department of Cell Biology and Morphology
Address: Rue du Bugnon 9, 1005 Lausanne
Tel: 021 692 52 56
GABAA receptor ligand binding modifications in a model of cortical malformation with epilepsy
Description of Project:
- Introduction : In spite of the recent development of new treatments, drug resistance remains a main concern in epilepsy management. Cortical malformations are frequent etiologies of drug-resistant seizures, some form of cortical dysembryogenesis being observed in 40% of intractable cases. Available animal models of cortical malformations are few and this represents a major limit in understanding precise mechanisms of abnormal cortical development and the associated lowered epileptic threshold. A new and unique autosomal recessive mouse model of cortical heterotopias (HeCo)1, characterized by a developmental delay and an increased tendency to epileptic seizures, result of a spontaneous mutation that appeared within the DBCM colony, will allow addressing fundamental questions regarding refractory epilepsy. Preliminary results showed a normal distribution of GABAA receptors subunits in the homotopic cerebral cortex above the malformation and a distribution of theses subunits within the heterotopias that was closely similar to the distribution of layer II-III. Nevertheless, data concerning the GABAA receptor subunit assembly and function are missing.
- Question / Aim of the work : To determine GABAA receptor binding within the hippocampus, homotopic cortex and cortical heterotopia of HeCo mutant and control mice.
- Techniques / methods applied : Autoradiographic imaging of diazepam-sensitive and diazepam-insensitive GABAA receptor binding using [3H]Ro 15-1788 (flumazenil) and the inverse agonist [3H]Ro 15-4513 (see reference 2)
- Expected outcome : Changes in binding characteristics of GABAA receptors within the hippocampus, homotopic cortex and/or cortical heterotopias will help to explain the lowered epileptic threshold of the mouse mutant HeCo.
1. Croquelois A, Giuliani F, Savary C, Kielar M, Amiot C, Schenk F, Welker E. Characterization of the HeCo mutant mouse: a new model of subcortical band heterotopia associated with seizures and behavioral deficits. Cereb Cortex. 2009 Mar;19(3):563-75.
2. Volk HA, Arabadzisz D, Fritschy JM, Brandt C, Bethmann K, Löscher W. Antiepileptic drug-resistant rats differ from drug-responsive rats in hippocampal neurodegeneration and GABA(A) receptor ligand binding in a model of temporal lobe epilepsy. Neurobiol Dis. 2006 Mar;21(3):633-46.
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