Role of neurotrophins and neuropeptides in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model for human generalized absence seizures

Abstract

Several studies have shown that neurotrophins and neuropeptides contribute to epileptogenesis but their impact on idiopathic generalized epilepsies is not yet elucidated. Generalized absence seizures are a specific type of epilepsy occurring predominantly in children. Sudden onset and termination of typical bilaterally synchronous 3Hz spike-and-wave discharges on the electroencephalogram and a brief impairment of consciousness with interruption of ongoing activity are hallmarks of this disease. New classes of absence drugs designed to block the process of epileptogenesis are needed because known treatments are not effective in all patients and a broad spectrum of adverse reactions has been described. Drug screening is hindered because the molecular mechanisms underlying generalized absence seizures are still not completely clarified. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) used in this study are a valid animal model that spontaneously displays many of the characteristics of human absence epilepsy. The aim of this thesis was to define the potential role of neurotrophins and neuropeptides in generalized absence seizures with special regard to expression differences between GAERS and control animals, changes during maturation and region-specific expression alterations. Additionally, the consequences of their application on seizure initiation and termination were studied. Brain-derived neurotrophic factor (BDNF) is ubiquitously expressed in brain and involved in several physiologic and pathologic processes including epilepsy. Glutamate release is enhanced, whereas inhibitory transmission is diminished by BDNF. Its signaling pathway is significantly impaired in adult GAERS after the onset of absence seizures due to reduced expression of BDNF receptors and transcription factors. Nevertheless, intracerebroventricular injection of BDNF significantly reduces the occurrence of spike-and-wave discharges in adult GAERS. Neuropeptides are cofactors of the classical neurotransmitters and therefore important modulators of neuronal excitability. Expression of the anticonvulsant agent neuropeptide Y (NPY) is directly influenced by BDNF. The density of NPY-expressing cells is clearly increased in GAERS compared to control animals. Additionally, the onset of absence seizures in adult GAERS is associated with a drastic decrease of brain NPY content. Application of NPY and agonists to its receptors efficiently suppresses spike-and-wave discharges in adult GAERS. In contrast, absences are evoked in juvenile GAERS following treatment with specific NPY receptor antagonists. In conclusion, this thesis demonstrates that BDNF as well as NPY exert potent antiabsence effects in adult GAERS. BDNF and NPY both represent accessible systems to intervene in brain excitability and thus provide new molecular targets for efficacious treatments against generalized absence epilepsy.