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Supply-rate depression as endogenous anti-epileptic mechanism

Objectif

Epilepsy is a prevalent neurological disorder affecting more than 1 % of all people, with the estimated number of 900,000 children and adolescents suffering from active epilepsy in Europe. Most current drugs targeting this disease have important adverse side-effects. An ideal drug would, however, potentiate the endogenous anti-seizure mechanisms that keep most humans epilepsy-free.

To date, these native “anti-seizure mechanisms” have not been identified. Recently, a novel candidate mechanism termed “supply-rate depression” was functionally characterized. It is only induced by excessive synaptic use, after which it dampens all pre-synaptic function for several minutes.

This proposal would test whether lowering the threshold for inducing supply-rate depression is protective against epilepsy using genetically engineered mice, and will additionally test a structure/function hypothesis related to the assembly of the vesicles in presynaptic terminal that could lead to a high-throughput drug screen.

These goals will be accomplished via the following Specific Aims:
1. To generate a synapsin 2 conditional knockout mouse line where synapsin 2 is deleted exclusively at excitatory synapses and thereby speed the onset of the protective mechanism at excitatory synapses.
2. To evaluate the susceptibility to seizures of the synapsin 2 conditional knockout mice using chemically induced models of epilepsy.
3. To apply state-of-the-art electron microscopy tomography techniques to test the structure/function hypothesis that the lengths of presynaptic vesicle tethering units are ~ 40% shorter in presynaptic terminals of synapsin 2 knockout synapses.

Results of this project may justify a large-scale industrial effort for developing a new generation of anti-epileptic drugs that target supply-rate depression. Thus, these new substances should have reduced occurrence and magnitude of unwanted side effects and would immensely improve the well-being of affected people.

Champ scientifique (EuroSciVoc)

Programme(s)

Thème(s)

Appel à propositions

FP7-PEOPLE-2012-CIG
Voir d’autres projets de cet appel

Régime de financement

MC-CIG - Support for training and career development of researcher (CIG)

Coordinateur

FYZIOLOGICKY USTAV AKADEMIE VED CESKE REPUBLIKY VEREJNA VYZKUMNA INSTITUCE (VVI)
Contribution de l’UE
Aucune donnée
Coût total
Aucune donnée

Participants (1)