A2A receptors control axon formation during neuronal development: new strategies to arrest epileptogenesis.

Overview

Project Summary

Epilepsy is an important pathology affecting 3% of the population. Current anti-epileptic drugs mostly control convulsions with a limited efficacy, and more importantly, they do not seize epileptogenesis. For instance, the prevention of epilepsy in patients at risk after acquired injury remains an unmet medical need. Besides, 30% of patients are drug refractory, mainly those with temporal lobe epilepsy (TLE). Thus, novel therapeutic strategies should be designed not only to control seizures, but also to arrest epileptogenesis. One of the structural-functional modifications taking place during epileptogenesis and contributing to recurrent spontaneous seizures is an abnormal axonal sprouting. Hippocampal mossy fibber (MF) sprouting found in patients and in animal models of temporal lobe epilepsy (TLE) is a very well characterised example of axonal sprouting observed in epilepsy. MF sprouting generates an aberrant excitatory feedback circuit in granule cells contributing to the hyperexcitability underlying the seizure-prone state. The prevention of it has been proposed as a strategy to control TLE. However, it is still not known the mechanism(s) underlying this aberrant re-wiring. This project tackles this need by proposing a straightforward hypothesis regarding the triggers and the mechanism of action responsible for this aberrant axonal sprouting. We now propose that this abnormal axonal sprouting is due to a reactivation of developmental-related mechanisms controlling axon formation/outgrowth, perhaps in an attempt to recover from a lesion (e.g. primary epileptogenic injury), but due to the inadequate context leads to an aberrant and deleterious re-wiring of the brain. Using this groundbreaking rationale, we now found a new signalling pathway that is involved in axon specification and outgrowth during development of hippocampal neurons that seems to be reactivated and operational during epileptogenesis. Indeed, our preliminary data show that this signalling pathway is involved in hippocampal MF sprouting in an animal model of TLE. Hence, in this project we will now characterize the contribution of this pathway to the hippocampal MF axonal sprouting and more importantly to the recurrent spontaneous seizures, the clinical hallmark of Epilepsy. This novel mechanistic hypothesis would constitute the first direct link between activity and neuronal cytoskeleton remodeling underlying the aberrant re-wiring observed in epileptogenesis. This multi-disciplinary project from molecules to behaviour will hopefully identify novel targets for therapeutic intervention to prevent or arrest epileptogenesis. Besides, the existence of a pathogenic reactivation in epileptogenesis of features characteristic of development would constitute a conceptual advance that opens new venues of research not only in epilepsy, but also in other brain disorders.

Main Goals

Characterize the molecular mechanisms underlying the aberrant hippocampal mossy fiber sprouting observed during epileptogenesis, supporting an hyperexcitability and seizure-prone state.

Project Details