Molecular characterization of febrile seizures and temporal lobe epilepsy : towards unraveling epileptogenesis and febrile seizure susceptibility

Abstract

Epilepsy is a neurological disorder that is characterized by recurrent seizures and affects about 1% of the population worldwide. Epilepsy can occur because of a genetic predisposition, because of acquired factors or because of a combination between the two (multifactorial). Temporal lobe epilepsy (TLE) is considered to be the most common partial epilepsy type with extensive etiological heterogeneity. Most cases probably can be classified as mulitfactorial. Although much progress has been made about the understanding of TLE, the molecular mechanisms involved in the etiology and neuropathology of TLE remain poorly understood. Febrile seizures (FS) are the most common initial precipitating event in mesial TLE (MTLE), but it is unclear whether FS themselves contribute to the development of MTLE, or whether a prenatal lesion, brain insult or a genetic predisposition is causal to both FS and MTLE . We demonstrate that the innate immune system plays an important role in human MTLE and that an acquired Navb3 channelopathy had developed in a subset of human MTLE patients. Chemokines were identified as highly regulated in human MTLE, and therefore the effects of these chemokines on hippocampal neurons were investigated. We showed that the chemokine CCL3 can alter neuronal activity and calcium dynamics in cultured hippocampal neurons by increasing NMDA receptor levels. To investigate the longitudinal effects of FS and to identify FS susceptibility genes we developed and validated two FS models in mice. We also showed that mouse FS susceptibility is influenced by a complex genetic background. Longitudinal effects of FS in the hippocampus were investigated using microarrays, which showed us that prolonged FS acutely induce transcriptional and heat-shock responses, and on the more long-term induce network reorganizations and reduced expression of Camk2a. FS susceptibility was investigated in more detail using a chromosome substitution mouse panel. We identified FS susceptibility loci on chromosomes 1, 2, 10, 13 and X. Using mice haploinsufficient for glutamine synthetase (Glul or GS), we characterized Glul as a major FS susceptibility gene. In the next sections results presented in this thesis are discussed in the context of MTLE, FS and epileptogenesis. These studies provide insight in the emerging role of the immune system in MTLE and identify genes and processes involved in FS and epileptogenesis. In human MTLE we identified high expression of chemokines, which in vitro increased neuronal activity. Blocking chemokines could prove beneficial to MTLE patients and is of interest for future studies. FS were shown to induce a process of epileptogenesis possibly culminating in MTLE in which Camk2a plays a key role. The role of Camk2a is currently being investigated in more detail. Although FS predispose to MTLE, we showed that genes influencing FS and epileptogenesis susceptibility are distinct. Glul was shown to be a major FS susceptibility gene and FS susceptibility loci have been localized to chromosomes 1, 2, 10, 13 and X of the A/J strain. Fine-mapping and subsequent sequencing will be necessary to identify causative genes and will increase our understanding of the FS/MTLE mechanisms and relationships.