The role of SHP-1 in deafferentation-induced neuronal death in the murine auditory brainstem

Deafferentation is the loss of sensory input from a portion of the body to the central nervous system (CNS), usually caused by interruption of the peripheral sensory fibers. Removal of afferent input, or changes in afferent activity, has been shown to have a dramatic impact on neuronal structure and function during a “critical period” of development in the auditory system. Inner ear cochlear ablation results in the death of anteroventral cochlear nucleus (AVCN) neurons from birth to approximately postnatal day 14 (P14) in the murine auditory brainstem. However, the underlying physiological mechanisms that define the critical period of deafferentation-induced neuronal death are still incompletely understood. Glial cells, especially microglia, have received much attention as being important CNS immunoregulatory cells and active participators in the pathogenesis of neuron damage during injury, infection, and neurodegenerative diseases. Increasing evidence has suggested that once activated, microglia are capable of inducing neuronal death by secreting neurotoxic substances. Whether microglial activation helps determine the critical period for deafferentation-induced neuronal death in the auditory brainstem remains to be elucidated. Activation of glia often involves phosphorylation events controlled by the antagonistic actions of protein tyrosine kinases and protein tyrosine phosphatases. SHP-1 is a cytoplasmic protein tyrosine phosphatase predominantly expressed in hematopoietic cells and has been implicated as a negative regulator in cytokine signaling as well as in the proliferation and differentiation of various cell types, including glia. These studies utilize the SHP-1 deficient motheaten (me/me) mouse model to investigate the role of SHP-1 and activated microglia in deafferentation-induced AVCN neuronal death. In vivo studies demonstrate that following cochlear ablation (1) there is an extended critical period (beyond P14) of neuron loss concomitant with exaggerated microglial activation in the me/me AVCN; and (2) a down-regulated expression of the anti-inflammatory cytokines IL-4 and IL-10 in combination with an up-regulated expression of the pro-inflammatory cytokine IL-1β in the injured me/me hindbrain post-ablation. In vitro studies corroborate the deleterious role of activated me/me microglia in contributing to neuronal death by demonstrating an increased release of neurocytotoxic substances by cultured me/me microglial cells.