Genes, Development And Behavior
Department of Translational Neuroscience
Utrecht, The Netherlands

Pierre de Graan

Position: emeritus Associate Professor (retired per June 1, 2017)
Phone: (+31) (0)88 75 61234
Phone reception: (+31) (0)88 75 68810



Current research aims (i) to identify susceptibility genes for febrile seizures in mouse models and (ii) for temporal lobe epilepsy in human cortical resection material. A particular focus is on genes involved in pharmaco-resistance and glutamatergic transmission.

Experimental strategy and key results:

Our research strategy is based on the notion that TLE can best be studied in hippocampus of TLE patients. In a long-term collaboration with clinicians in the UMCU we investigate the pathogenesis of temporal lobe epilepsy (TLE) in hippocampal and cortical biopsy material (> 300 samples) removed during surgical resection of the epileptic focus of patients with pharmaco-resistant TLE. By comparing hippocampal micro-array gene expression profiles of TLE patients with different etiologies (for instance with and without a febrile seizures history) and autopsy controls, we search for affected genes and pathways.

Gene ontology analysis has identified genes involved in immunity and defense and in protein protection and degradation. Microarray data have been verified with q-PCR and in situ hybridization.. In the second approach we perform longitudinal expression profiling of the hippocampus of mice at different times after induction of febrile convulsions, especially in the latent phase where spontaneous seizures do not occur yet. In a forward genetic strategy we use mouse chromosome substitution and recombinant inbred strains to identify QTLs and genes contributing to seizure susceptibility. Using a combination of back cross techniques and microarray analysis, we aim to identify seizure susceptibility genes. By comparing the data from all three approaches we will select and further investigate the human susceptibility genes. This knowledge will be used to perform SNP analysis on human patient material available in our own collection and through various collaborations. We are now performing an association study in human TLE patients analyzing candidate genes identified in the microarray screen.

Recent key publications

1: Proper, E.A., Oestreicher, A.B., Jansen, G., Van Veelen, C.W.M., Van Rijen, P.C., Gispen, W.H. and De Graan, P.N.E. (2000). Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 123, 19-30.

2: Proper, E.A., Hoogland, G., Kappen, S., Jansen, G.H., Rensen, M., Schrama, L.H.,Van Veelen, C.W.M., Van Rijen, P.C., Van Nieuwenhuizen, O., Gispen, W.H. and De Graan, P.N.E. (2002)Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125, 32-43

3: Van der Hel, S., Notenboom, R.G.E., Bos, I.W.M., Van Rijen, P.C., Van Veelen, C.W.M. and De Graan, P.N.E. (2005) Reduced hippocampal glutamine synthetase activity in temporal lobe epilepsy patients is associated with neuronal cell loss. Neurology 64, 326-333 .

4: Notenboom, R.G.E., Hampson, D.R., Jansen, G.G., van Rijen, P.C., van Veelen, C.W.M., van Nieuwenhuizen, O. and de Graan, P.N.E.. (2006) Up-regulation of hippocampal metabotropic glutamate receptor 5 in temporal lobe epilepsy patients. Brain 129, 96-107