Loss of neuronal activity facilitates surface accumulation of p75NTR and cell death in avian cochlear nucleus.

Abstract

Sensorineural hearing loss causes cell death in central auditory neurons, but molecular mechanisms of triggering this process are not fully understood. We report here that loss of afferent activity promotes cell death by facilitating proBDNF-p75NTR signals in cochlear nucleus of chicks around hatch. RNA-seq analyses revealed up-regulation of genes related to proBDNF-p75NTR-JNK signals as well as apoptosis at the nucleus within 24hours after unilateral cochlea deprivation. Western blotting confirmed a high level of proBDNF protein at the nucleus. Moreover, FLAG-tagged p75NTR accumulated at the plasma membrane of the neurons within 6hours after the deprivation, well before the upregulation of apoptotic genes. Cell viability assay using propidium iodide in organ culture showed that proBDNF increased the fraction of dying neurons in a dose-dependent manner. In addition, pharmacological blockades of synaptic and spike activities in the culture reproduced the surface accumulation of p75NTR in vivo and increased the fraction of dying neurons, while genetic inhibition of p75NTR signals occluded the cell death during the activity blockades. These results indicate that afferent activity is crucial for suppressing surface accumulation of p75NTR and hence proBDNF-p75NTR signals and that the loss of this suppression would contribute to triggering cell death after deafferentation in the developing brainstem auditory circuit.