AMPA receptor-mediated, calcium-dependent CREB phosphorylation in a subpopulation of auditory neurons surviving activity deprivation

Although dependence on afferent synaptic activity has been shown for centra l neurons in every sensory system, the mechanisms of afferent maintenance o f target sensory neurons are not understood. Neurons in the cochlear nucleu s (CN) require afferent activity for maintenance and survival. One of the e arliest changes seen after activity deprivation is an increase in intracell ular calcium that leads to the death of 30% of the neuronal population. Six ty minutes after deafferentation, the surviving neurons show increased phos phorylation of the transcription factor calcium/cAMP response element-bindi ng protein (CREB). CREB phosphorylation in activity-deprived CN neurons is dependent on increased intracellular calcium resulting from influx through AMPA receptors and is mediated by calcium/calmodulin-dependent kinases and protein kinase A. We conclude that in CN neurons, the deafferentation-induc ed increase in calcium activates at least two kinase pathways that phosphor ylate CREB in surviving neurons. We hypothesize that this phosphorylation r esults in the transcription of genes containing the calcium/cAMP response e lement within their promoter regions, and these genes code for proteins tha t allow the neurons to compensate for their hypercalcemic, activity-deprive d state.