Lithium increases bcl-2 expression in chick cochlear nucleus and protects against deafferentation-induced cell death

Abstract

Approximately 20-30% of neurons in the avian cochlear nucleus (nucleus magnocellularis) die following deafferentation (i.e. deafness produced by cochlea removal) and the remaining neurons show a decrease in soma size. Cell death is generally accepted to be a highly regulated process involving various pro-survival and pro-death molecules. One treatment that has been shown to modify the expression of these molecules is chronic administration of lithium. The present experiments examined whether lithium treatment can protect neurons from deafferentation-induced cell death. Post-hatch chicks were treated with LiCl or saline for 17 consecutive days, beginning on the day of hatching. On the 17th day, a unilateral cochlea ablation was performed. Five days following surgery, the nucleus magnocellularis neurons were counted stereologically on opposite sides of the same brains. Lithium reduced deafferentation-induced cell death by more than 50% (9.8% cell death as compared with 22.4% in saline-treated subjects). Lithium did not affect cell number on the intact side of the brain. Lithium also did not prevent the deafferentation-induced decrease in soma size, suggesting a dissociation between the mechanisms involved in the afferent control of soma size and those involved in the afferent control of cell viability. A possible mechanism for lithium's neuroprotective influence was examined in a second set of subjects. Previous studies suggest that the pro-survival molecule, bcl-2, may play a role in regulating cell death following deafferentation. Tissues from lithium-and saline-treated subjects were examined using immunocytochemistry. Chronic administration of lithium dramatically increased the expression of bcl-2 protein in nucleus magnocellularis neurons. These data suggest that lithium may impart its neuroprotective effect by altering the expression of molecules that regulate cell death. Keywords apoptosis; neuroprotection; auditory brainstemCell death is a regulated process that is common during normal development of the nervous system, but can be initiated by a variety of events including deafferentation, disease, or injury. Neuronal cell death can also be induced during development in many sensory systems following the loss of sensory input. For example, mitral and tufted cells of the olfactory system die following unilateral naris occlusion (Frazier and Brunjes, 1988;Meisami and Safari, 1981), and in the visual system, the survival of tectal neurons depends on activity-dependent release of trophic factors from retinotectal axon terminals (Catsicas et al., 1992). In the auditory system, cell death can occur in the cochlear nucleus following deafness (Born and Rubel, 1985;Hashisaki and Rubel, 1989;Tierney et al., 1997). Although cell death following sensory deprivation has been widely studied in a variety of systems, little work has gone into efforts *Corresponding author. Tel: +1-850-644-1200; fax: +1-850-644-7739. E-mail address: hyson@psy.fsu.edu (R. L. Hyson).. The present experiments examine the control of cel...

The influence of chronic lithium administration on deafferentation-induced cellular changes in the chick cochlear nucleus

“…Only 0.8% of the deafferented NM neurons would be considered labeled in brains from lithium-treated subjects. The 0.8% of labeled cells may seem somewhat low since Bush and Hyson (2006) did report some cell death in the lithium-treated subjects. One possible explanation of this discrepancy is that the effects of lithium in the present experiment were evaluated on the same day as cochlea removal.…”

“…Previous work (Bush and Hyson, 2006) showed that chronic lithium administration protected NM neurons from deafferentation-induced cell death, but did not prevent the deafferentation-induced reduction in soma size. The present sets of experiments examined different events that occur in the cell death cascade in deafferented NM neurons to determine which of these events are influenced by chronic lithium administration.…”

“…The dose of LiCl was gradually increased across age, beginning at 1.5 mEq/kg for the first four days, followed by 2.3 mEq/kg for seven days, and finally, 3.0 mEq/kg for the last six days. This schedule was identical to that used by Bush and Hyson (2006) and adapted from the protocols of both Wei et al (2001) and Nonaka and Chuang (1998). The volume of each injection was 1 ml/kg.…”

“…Additionally, lithium has been shown to be effective in preventing toxic increases in intracellular calcium (Okamoto et al, 1994). Bush and Hyson (2006) found that chronic lithium administration was effective at increasing Bcl-2 protein expression in NM neurons and that this treatment protected the neurons from deafferentation-induced cell death.…”

“…Bush and Hyson (2006) hypothesized that if Bcl-2 protein was upregulated prior to cochlea removal, then NM neurons might be protected from deafferentation-induced cell death. To test this hypothesis, they chronically administered lithium to posthatch chicks prior to cochlea removal.…”