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Alexandre Croquelois

PI of the laboratory: Alexandre Croquelois
Tél: 021 314 14 76
Email: alexandre.croquelois@unil.ch

Direct supervisor (assistant): Michel Kielar
Tél: 021 692 51 34,
Email: michel.kielar@unil.ch

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.

- References:
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.

Link to the group web site

Rue du Bugnon 9 - CH-1005 Lausanne  - Switzerland  -  Tel. +41 21 692 51 00  -  Fax +41 21 692 51 05
Swiss University