Gene expression differences over a critical period of afferent-dependent neuron survival in the mouse auditory brainstem

Abstract

Deprivation of auditory nerve input in young mice results in dramatic neuron death in the anteroventral cochlear nucleus (CN), while the same manipulation performed in older mice does not result in significant neuronal loss. The molecular basis underlying this critical period of susceptibility to loss of afferent input remains largely unknown. One possibility is that developmental differences in baseline mRNA expression of specific genes could predispose CN neurons to either death or survival after deafferentation. We used two microarray platforms to identify differentially expressed genes in the CN during and after this critical period. Results across platforms were also compared to each other. Three ages were examined; during the critical period (postnatal day (P)7), at the closing of the critical period (P14), and 1 week after the critical period (P21). Of all the genes surveyed (22,690 or 15,247), 1,082 were identified as significantly changed in expression during the critical period relative to after. Real-time reverse transcription polymerase chain reaction and immunohistochemistry confirmed and extended the microarray results for a subset of these genes. Further analysis of genes related to apoptotic pathways showed 6 out of 7 differentially expressed known pro-apoptotic genes had higher expression during the critical period. In contrast, 9 out of 11 differentially expressed known pro-survival genes increased after the critical period when CN neurons survive deprivation. This finding supports the concept that multiple neuroprotective mechanisms increase and pro-apoptotic factors decrease over development to protect mature neurons from stressful insults, making them less dependent on afferent input for survival.

Time-dependent Gene Expression Analysis of the Developing Superior Olivary Complex

“…A similar drop in differentially expressed genes during postnatal development could also be observed in microarray data obtained for the cochlear nucleus complex, another auditory brainstem structure. In this tissue, 6.2% of 22,690 oligos were differentially expressed between P7 and P14, and 0.13% were differentially expressed between P14 and P21, using criteria similar to ours (p Յ 0.05 and fc of Ն1.8) (32). Comparing all stages in the SOC, the largest number of differentially expressed oligos was observed between P0 and P25 (5,373 oligos, ϳ13.1%) ( Table 1).…”

Deafferentation-Induced Activation of NFAT (Nuclear Factor of Activated T-Cells) in Cochlear Nucleus Neurons during a Developmental Critical Period: A Role for NFATc4-Dependent Apoptosis in the CNS

“…This implies that bcl-2 may be inhibiting the upregulation of FasL expression that follows deafferentation of AVCN neurons that are beyond the critical period, ultimately preventing their death by suppressing the Fas/ FasL apoptotic pathway. Similarly, Harris et al (2005) found, using microarray analysis, that AVCN from mice within the critical period express higher levels of transcript for proapoptotic genes than AVCN from mice beyond the critical period and, conversely, AVCN from mice beyond the critical period express higher levels of transcript for prosurvival genes than AVCN from mice within the critical period. This indicates a developmental "switch" in AVCN from a complement of cellular mechanisms favoring induction of an apoptotic pathway to a complement of mechanisms that prevent or eliminate the apoptotic pathways.…”

“…During maturation, the neurons undergo a transformation from being susceptible to deafferentation-induced death to being resistant to the same manipulation. The biological switch that transforms the way in which these neurons respond to removal of afferent input is yet to be characterized, although many likely cellular and molecular candidates have been suggested in both the auditory (Rubel et al, 2004;Harris et al, 2005) and visual (Taha and Stryker, 2005) systems.…”

“…It is therefore plausible to hypothesize that this increase in [Ca 2ϩ ] i causes a cascade of calcium-mediated intracellular signaling events that elicit a sur-vival or death response in AVCN neurons within the critical period but not beyond. Therefore, a cellular mechanism must exist that differentiates the response to increased [Ca 2ϩ ] i during the critical period, but no longer functions in this context, is functionally offset by a different intracellular environment because of development (e.g., different gene products and proteins as suggested by Harris and Rubel, 2005), or no longer exists after the critical period.…”

The Cochlear Implant in Action: Molecular Changes Induced in the Rat Central Auditory System

“…However, important differences exist between juvenile and adult brain plasticity with respect to speed, breadth, and type of changes inducible by internal or external stimuli (e.g. Harris et al, 2005;2008). At all developmental stages, neuroplasticity has many facets and includes the mutability on virtually all levels of neuronal organization, including volume growth, modifications of topographical maps, axon rerouting, dendritic outgrowth or retraction, cell death, mitosis, synaptogenesis, and molecular changes of various sorts.…”