bcl-2 Overexpression Eliminates Deprivation-Induced Cell Death of Brainstem Auditory Neurons

Abstract

Deprivation of afferent input in young animals results in transneuronal degeneration of postsynaptic sensory neurons in a variety of species and sensory pathways. Transneuronal degeneration is generally not seen in adult animals. The cellular and molecular basis for this dramatic developmental change in susceptibility is not understood. One possibility is that genes involved in the apoptotic process are involved in determining cell death or survival after afferent deprivation. To further investigate this possibility, we performed unilateral cochlear ablation on wild-type and bcl-2-overexpressing mice at a variety of ages. In postnatal day 5 (P5) or P8 wild-type mice, cochlea removal resulted in a 54% or 31% neuronal loss in the anteroventral cochlear nucleus (AVCN), respectively. When the same manipulation is performed on a P30 mouse, no loss of AVCN neurons occurs. This confirmed a rather abrupt change in the sensitivity to disruption of afferent input, a critical period. However, in littermates expressing bcl-2 under a neuron-specific enolase promoter, no significant loss of AVCN neurons was observed at any age after unilateral cochlear ablation. Furthermore, wild-type mice demonstrate rapid expression of activated caspase-3 in AVCN neurons within hours of deafferentation, whereas bcl-2-overexpressing mice do not. This suggests that bcl-2 can influence cell survival after removal of afferent input during the critical period and is consistent with the hypothesis that caspase-3 is one effector of cell death under these circumstances. These data are the first to indicate that known apoptotic mediators can play a role in central neuronal plasticity in models of afferent deprivation.

Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells

“…The survival promoting action of VIIIth nerve activity relies on stimulation of metabotropic glutamate receptors, which act to keep [Ca 2ϩ ] i in cochlear neurons at low levels (639). Neuronal cell death appears to involve activation of caspase-3 (429). These studies demonstrate an intimate relationship between developmental patterns of spontaneous activity, the resulting activity in the VIIIth nerve, and neuronal cell survival in the auditory brain stem.…”

Development and regeneration of hair cells share common functional features

“…Previous studies have demonstrated that cochlea removal impacts CN neural survival and atrophy in neonatal and adult chickens as well as in other mammalian models (2), raising the intriguing assertion that there is a sustained trophic interaction between the cochlea and CN neurons. Nonetheless, there appears to be a critical window when removal of inputs from the cochlea induces robust cell death in the CN (45), suggesting that susceptibility to afferent deprivation may potentially depend on a molecular switch (46). Thus, the challenges for newly regenerated HCs are not only to establish a synaptic niche with spiral ganglion neurons but also to resume their position in the tonotopic map of the CN to mediate the survival of neurons.…”

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

“…Presumably, if bcl-2 protein was expressed, it could have a neuroprotective influence. Indeed, bcl-2 has been implicated as having a neuroprotective effect in mammalian cochlear nucleus neurons following deafferentation (Mostafapour et al, 2002). Based on these studies, one would expect that if bcl-2 protein were upregulated prior to cochlea removal, then fewer cells would die.…”

“…A limited number of treatments have been shown to protect spiral ganglion cells from cell death following cochlear damage (Yamagata et al, 2004). For brain stem auditory neurons, the only promising manipulations reported to date involve either embryonic treatment with receptor antagonists (Solum et al, 1997) or genetic manipulations (Mostafapour et al, 2002).…”