The proposed experiments are directed at elucidating the mechanism of survival in activity-deprived auditory neurons. As with central neurons in all other sensory systems, brainstem auditory neurons require afferent input for maintenance and survival. Elimination of this input results in the death of 30- 60 percent of cochlear nucleus neurons in neonatal chicks and mice. Thus, the proposed studies concern the role of phosphorylation and activation of the transcription factor calcium/cAMP response element binding protein (CREB) in the subpopulation of cochlear nucleus neurons that survive activity deprivation. The experiments will address two groups of questions about the interactions among activity deprivation, intracellular calcium changes, CREB phosphorylation and activation, and neuronal survival. The hypothesis driving these experiments posits that following activity deprivation cochlear nucleus neurons show increased phophorylation/activation of CREB in the response to increased intracellular calcium. This phosphorylation is mediated by calcium-dependent activation of calcium/calmodulin dependent kinases and protein kinase A. Once phosphorylated, CREB results in the transcription of genes containing the calcium/cAMP response element within their promoter region, and the protein products of some of these genes allow the neurons to survive activity deprivation. The proposed experiments, grouped into two specific aims, will characterize the mechanisms of CREB phosphorylation and the role of this phosphorylation in neuronal survival. Neuronal survival is a critical issue in patients with sensory deficits. A significant fraction of the U.S. population suffers from profound hearing loss of early onset. There is agreement that early intervention is the most effective strategy for successful treatment. Understanding the mechanisms of neuronal survival following early sensorineural hearing loss may influence the success of restorative therapies for the congenitally hearing-impaired. During neural development, critical periods occur in which central structures are more sensitive or receptive to changes in afferent input. One potential benefit to understanding how central neurons survive activity deprivation will be to prolong these critical periods, thus improving success rates of early intervention therapy on patients with congenital hearing deficits. The proposed experiments would contribute information about how central auditory neurons survive in the absence of afferent input.
|Luoma, Jessie I; Zirpel, Lance (2008) Deafferentation-induced activation of NFAT (nuclear factor of activated T-cells) in cochlear nucleus neurons during a developmental critical period: a role for NFATc4-dependent apoptosis in the CNS. J Neurosci 28:3159-69|