Annals of Medicine. Epilepsy is no longer one of these mysterious afflictions that people during Middle Ages would cure by trepanating or even beheading, to make the Evil go. Here, the authors showed that the brain of adult rat was more susceptible to develop seizures if the precursor of neurotrophic factor proBDNF was artificially raised, for ever fixed in its immature state. Meanwhile, neurons exhibited hallmarks of immaturity too such as a low expression of KCC2 and a depolarizing action of GABA. These findings suggest new directions for developing a 2.0 therapy. (Ingrid Bureau)
Authors of the publication: B. Riffault, N. Kourdougli, C. Dumon, N. Ferrand, E. Buhler, F. Schaller, C. Chambon, C. Rivera, J.-L. Gaiarsa & C. Porcher
SCIENTIFIC ABSTRACT: he brain-derived neurotrophic factor (BDNF) is synthesized as a precursor, namely proBDNF, which can be processed into mature BDNF (mBDNF). Evidences suggest that proBDNF signaling through p75NTR may account for the emergence of neurological disorders. These findings support the view that the relative availability of mBDNF and proBDNF forms is an important mechanism underlying brain circuit formation and cognitive functions. Here we describe novel insights into the proBDNF/p75NTR mechanisms and function in vivo in modulating neuronal circuit and synaptic plasticity during the first postnatal weeks in rats. Our results showed that increased proBDNF/p75NTR signaling during development maintains a depolarizing γ-aminobutyric acid (GABA) response in a KCC2-dependent manner in mature neuronal cells. This resulted in altered excitation/inhibition balance and enhanced neuronal network activity. The enhanced proBDNF/p75NTR signaling ultimately led to increased seizure susceptibility that was abolished by in vivo injection of function blocking p75NTR antibody. Altogether, our study shed new light on how proBDNF/p75NTR signaling can orchestrate the GABA excitatory/inhibitory developmental sequence leading to depolarizing and excitatory actions of GABA in adulthood and subsequent epileptic disorders.
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