Seizures tip the balance of neurotrophin signaling toward neuronal death

Abstract

Neurotrophins and proneurotrophins have opposing actions on neuronal survival, mediated by their respective receptors. Trk receptors are necessary for mature neurotrophins to support neuronal survival, while the p75 neurotrophin receptor (p75NTR) mediates proneurotrophin-induced apoptosis. Therefore, the consequences of neurotrophin actions depend on expression of the different neurotrophin receptors; regulation of proneurotrophin cleavage, which can determine which receptor is bound; and activation of downstream signaling events supporting neuronal survival or apoptosis. Several types of brain injury, including seizures, lead to altered levels of neurotrophin receptors, with increased neuronal expression of p75NTR in the brain. Seizure-induced injury also leads to increased secreted proNGF due to altered regulation of the extracellular proNGF-cleaving enzymes. Downstream signaling pathways triggered by proNGF activation of p75NTR include induction of the phosphatase PTEN, which antagonizes TrkB signaling triggered by BDNF and prevents the activation of Akt. Thus, the increase in extracellular proNGF and elevated levels of p75NTR that occur after injury create a milieu that leads to neuronal death.