Prosurvival and proapoptotic intracellular signaling in rat spiral ganglion neurons in vivo after the loss of hair cells.

Neurons depend on afferent input for survival. Rats were given daily kanamycin injections from P8 to P16 to destroy hair cells, the sole afferent input to spiral ganglion neurons (SGNs). Most SGNs die over an approximately 14-week period after deafferentation. During this period, the SGN population is heterogeneous. At any given time, some SGNs exhibit apoptotic markers--TUNEL and cytochrome c loss--whereas others appear nonapoptotic. We asked whether differences among SGNs in intracellular signaling relevant to apoptotic regulation could account for this heterogeneity. cAMP response element binding protein (CREB) phosphorylation, which reflects neurotrophic signaling, is reduced in many SGNs at P16, P23, and P32, when SGNs begin to die. In particular, nearly all apoptotic SGNs exhibit reduced phospho-CREB, implying that apoptosis is due to insufficient neurotrophic support. However, >32% of SGNs maintain high phospho-CREB levels, implying access to neurotrophic support. By P60, when approximately 50% of the SGNs have died, phospho-CREB levels in surviving neurons are not reduced, and SGN death is no longer correlated with reduced phospho-CREB. Activity in the proapoptotic Jun N-terminal kinase (JNK)-Jun signaling pathway is elevated in SGNs during the cell death period. This too is heterogeneous: <42% of the SGNs exhibited high phospho-Jun levels, but nearly all SGNs undergoing apoptosis exhibited elevated phospho-Jun. Thus, heterogeneity among SGNs in prosurvival and proapoptotic signaling is correlated with apoptosis. SGN death following deafferentation has an early phase in which apoptosis is correlated with reduced phospho-CREB and a later phase in which it is not. Proapoptotic JNK-Jun signaling is tightly correlated with SGN apoptosis.