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

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.