Patterns of cell death in mouse anteroventral cochlear nucleus neurons after unilateral cochlea removal

Abstract

Developmental changes that influence the results of removal of afferent input on the survival of neurons of the anteroventral cochlear nucleus (AVCN) of mice were examined with the hope of providing a suitable model for understanding the cellular and molecular basis for these developmental changes in susceptibility. We performed unilateral cochlear ablation on wild-type mice at a variety of ages around the time of hearing onset to determine developmental changes in the sensitivity of AVCN neurons to afferent deprivation. In postnatal day 5 (P5) mice, cochlea removal resulted in 61% neuronal loss in the AVCN. By age P14, fewer than 1% of AVCN neurons were lost after this manipulation. This reveals a rather abrupt change in the sensitivity to disruption of afferent input, a critical period. We next investigated the temporal events associated with neuron loss after cochlea removal in susceptible animals. We demonstrate that significant cell loss occurs within 48 hours of cochlea removal in P7 animals. Furthermore, evidence of apoptosis was observed within 12 hours of cochlea removal, suggesting that the molecular events leading to cell loss after afferent deprivation begin to occur within hours of cochlea removal. Finally, we began to examine the role of the bcl-2 gene family in regulating afferent deprivation-induced cell death in the mouse AVCN. AVCN neurons in mature bcl-2 knockout mice demonstrate susceptibility to removal of afferent input comparable to neonatal sensitivity of wild-type controls. These data suggest that bcl-2 is one effector of cell survival as these cells switch from afferent-dependent to -independent survival mechanisms.

Presynaptic maturation in auditory hair cells requires a critical period of sensory-independent spiking activity

“…This is also suggested by the observation that the specific firing pattern is unlikely to influence the maturation of the synaptic machinery since both linear (mouse) (14) and high-order relations (gerbil) (13) can develop from immature apical coil IHCs that show a similar bursting firing pattern (10). Instead, tonotopic gradients in the spiking activity during the first postnatal week could influence additional aspects of auditory development, such as promoting the tonotopic differentiation of auditory neural circuits to and from the brain, which are known to be mainly established during this early period (12,45,46). The persistence of spontaneous activity in the second week, with a tightly regulated waveform and frequency, seems to drive the intrinsic functional maturation of IHC ribbon synapses in preparation for their transition into graded sensory receptors at P12.…”

Spontaneous activity in the developing auditory system

“…The most consistent observation is that depriving SGNs of excitatory input, through either cochlear removal, IHC degeneration, or through use of genetic models that exhibit impaired Ca 2+ -dependent glutamate release from IHCs, leads to apoptotic degeneration of SGNs and neurons in the ventral cochlear nuclei (Hashisaki and Rubel 1989;Mostafapour et al 2000;Glueckert et al 2003;Harris and Rubel 2006;Seal et al 2008;Hirtz et al 2011). In the CNS, more severe neuronal loss was observed when cochlear input was eliminated during the pre-hearing period, while no degeneration was observed when the cochlea was ablated after the onset of hearing (Hashisaki and Rubel 1989;Tierney et al 1997;Mostafapour et al 2000), suggesting that there is a critical period of development, prior to sensory experience, when afferent activity from IHCs supports neuronal survival.…”

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

“…Functional deafferentation, either by cochlear ablation or block of VIIIth nerve activity, causes pronounced and rapid neuronal death in the cochlear nucleus (see Ref. 428), with first events in the postsynaptic cells visible within 12 h. These effects are specific to developing animals and can be rescued by providing synaptic activity onto cochlear neurons but not by stimulating them directly. 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).…”