GENE EXPRESSION IN THE COURSE OF EPILEPTOGENESIS

Fernando Lopes da Silva, M.D., Ph.D.; Emeritus Professor
Center of NeuroSciences, Swammerdam Institute for Life Sciences
University of Amsterdam

           In order to get insight into the mechanisms that may lead to the development and progression of temporal lobe epilepsy (TLE), the dynamics of gene expression during epileptogenesis in the rat post-status epilepticus (SE) model of TLE can yield interesting information. Gene expression analysis was performed using the Affymetrics Gene Chip System (RAE230A), and  GENMAPP and Gene Ontology were used to identify global biological trends in gene expression data in the entorhinal cortex and hippocampus at three times after SE: acute - 1 day, latent phase - 1 week and chronic phase - about 3 months. The immune response is the most prominent process changed during all three phases of epileptogenesis. Synaptic transmission is a downregulated process during the acute and latent phase. GABA receptor subunits involved in tonic inhibition are persistently downregulated, in particular the genes that encode á5 and the ä GABA receptor subunit are most dramatically downregulated (around 2 fold).  Rats that were stimulated but that did not develop spontaneous seizures later on, had also some changes in gene expression but this is not reflected in a significant change of specific  biological rocesses. These data suggest that the targeting of specific genes that are involved in these biological processes may be a promising strategy to slow down or prevent the progression of epilepsy.Especially genes related to the immune  response, such as complement factors, interleukins, and genes related to rostaglandin synthesis and coagulation pathway may be interesting targets The lectures and practical discussions will address the question of how epileptogenesis  takes place with the focus on changes of gene expression in a rat model of temporal lobe epilepsy. At the end the students should be able of interpreting the neurobiological mechanisms underlying epileptogenesis, and of understanding how micro-arrays analysis can  unravel changes in gene expression; furthermore they will be able to critical analyse how large amounts of gene expression data can be processed in order to obtain relevant information, that may be used in clinical applications.