ENDOGENOUS AED · Supply-rate depression as endogenous anti-epileptic mechanism
FP7 — People (Marie Curie Actions)
- Duration
- 2012-09-01 → 2017-08-24
- EU contribution
- €100,000
- Participants
- 2
- Scheme
- MC-CIG
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Results in brief
Periodic Report Summary 1 - ENDOGENOUS AED (Supply-rate depression as endogenous anti-epileptic mechanism)
The Objectives from the original project with the acronym “Endogenous AED” were not achieved. The summary from the proposed updated project are described instead. The work on the updated project is in progress: Epilepsy is a prevalent neurological disorder characterized by seizures that affects more than 1% of all people, with the estimated number of 900,000 children and adolescents suffering from active epilepsy in Europe. The main target of my project is a protein called kainate receptor, which is present at the points of contact between nerve cells called synapses. An overwhelming amount of data implicates the activation of postsynaptic kainate receptors (KARs) in epileptogenesis. My goal was to explore an unusual way in which kainate receptor activity can strengthen the synaptic connections, which normally serves to increase the power of our brains to learn and memorize new things. I was planning to test whether this, otherwise beneficial process, can be misused, making the brain more prone to initiate epileptic seizures. Indeed, the epileptic seizures lead to numerous functional changes and morphological rearrangements in synapses. My plan was to test whether this applies to the processes mediated by kainate receptors, as well, and if so, I was planning to try to find the way to impede and prevent such misuse, which would indicate a new strategy in fight against epilepsy and its devastating consequences. To test whether strengthening of synapses mediated by kainate receptors can also be hijacked by pathological process, I was planning to imitate epileptic seizures in isolated nerve tissue. Finally, I wanted to test if it also occurs during actual epileptic seizures in the brain and, more importantly, whether seizures can be prevented or ameliorated by interfering with the peculiar signalling of kainate receptors. Untangling the interactions between kainate receptors and other types of receptor proteins in the brain could not only tell us more about the inner workings of a healthy brain, but also provide a practical insight towards molecular events whose modification can be a target of new substances that could protect against epilepsy or help to cure it. Working on this project was supposed to allow me to devote my time to training younger scientists, as well as to explore opportunities to form my own lab, in order to continue the collaboration with fellow neuroscientists. With the successful completion of the project, I was planning to open new branches of research that will serve to further integrate me within the neuroscience research community.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
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Data: CORDIS, © European Union