Altered Chloride homeostasis in Reactive plasticity upOn BrAin Trauma

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Traumatic brain injuries are the main injury-related causes of permanent disability, and arethe third leading cause of mortality in Europe. Worldwide, more than 10 million people areaffected every year. Post-traumatic epilepsy is the most common cause of new-onsetepilepsy in young adults; following penetrating brain wounds, the likelihood of developingepilepsy is more than 50%. 30 to 40% of patients with post-traumatic epilepsy have seizuresthat are incompletely controlled with currently available medication. Moreover, unnecessarytreatment with currently available antiepileptic drugs may then impair neurorehabilitation afterbrain trauma. It is evident that this field desperately needs new therapeutically relevanttargets. In order to find them, we need to understand in detail the mechanisms engagedupon brain trauma. In this proposal, five European groups, with expertise ranging fromcellular to systems Neuroscience, will pursue a common aim: to disclose the mechanismsand impact of trauma-induced changes in inhibitory neurotransmission in the cortex.Preliminary results from our collaborators suggest a working hypothesis in which a majorcomponent of altered inhibitory neurotransmission upon brain trauma is themalfunction of proteins involved in chloride transport in neurons. Subsequentabnormalities in neuronal chloride regulation not only perturb inhibitory signals, but alsoappear to be crucial for post-traumatic neuronal survival and proliferation, leading to alteredactivity of neuronal networks. Thus, the multifaceted impact of chloride transport malfunctionin neurons makes it a particularly promising target with strong potential for innovativetherapeutic strategies to improve rehabilitation of brain trauma patients in the future.