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The Journal of Neuroscience, October 22, 2008, 28(43):10990-11002; doi:10.1523/JNEUROSCI.2697-08.2008

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Development/Plasticity/Repair
Afferent Deprivation Elicits a Transcriptional Response Associated with Neuronal Survival after a Critical Period in the Mouse Cochlear Nucleus

Julie A. Harris,^1,2 Fukuichiro Iguchi,¹ Armin H. Seidl,¹ Diana I. Lurie,³ and Edwin W Rubel^1,2

¹Department of Otolaryngology, Head and Neck Surgery, Virginia Merrill Bloedel Hearing Research Center, and ²Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington 98195, and ³Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana 59812

Correspondence should be addressed to Dr. Edwin W Rubel, Virginia Merrill Bloedel Hearing Research Center, Box 357923, CHDD Bldg, Rm CD176, University of Washington, Seattle, WA 98195-7923. Email: rubel{at}u.washington.edu

The mechanisms underlying enhanced plasticity of synaptic connections and susceptibilities to manipulations of afferent activity in developing sensory systems are not well understood. One example is the rapid and dramatic neuron death that occurs after removal of afferent input to the cochlear nucleus (CN) of young mammals and birds. The molecular basis of this critical period of neuronal vulnerability and the transition to survival independent of afferent input remains to be defined. Here we used microarray analyses, real-time reverse transcription PCR, and immunohistochemistry of the mouse CN to show that deafferentation results in strikingly different sets of regulated genes in vulnerable [postnatal day (P) 7] and invulnerable (P21) CN. An unexpectedly large set of immune-related genes was induced by afferent deprivation after the critical period, which corresponded with glial proliferation over the same time frame. Apoptotic gene expression was not highly regulated in the vulnerable CN after afferent deprivation but, surprisingly, did increase after deafferentation at P21, when all neurons ultimately survive. Pharmacological activity blockade in the eighth nerve mimicked afferent deprivation for only a subset of the afferent deprivation regulated genes, indicating the presence of an additional factor not dependent on action potential-mediated signaling that is also responsible for transcriptional changes. Overall, our results suggest that the cell death machinery during this critical period is mainly constitutive, whereas after the critical period neuronal survival could be actively promoted by both constitutive and induced gene expression.

Key words: microarray; critical period; cochlear nucleus; activity-dependent; apoptosis; deafferentation; stability

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Received June 12, 2008; revised Aug. 11, 2008; accepted Sept. 23, 2008.

Correspondence should be addressed to Dr. Edwin W Rubel, Virginia Merrill Bloedel Hearing Research Center, Box 357923, CHDD Bldg, Rm CD176, University of Washington, Seattle, WA 98195-7923. Email: rubel{at}u.washington.edu

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