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Cerebral Cortex Advance Access originally published online on December 5, 2007
Cerebral Cortex 2008 18(8):1799-1813; doi:10.1093/cercor/bhm206
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© The Author 2007. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Cochlear Implants Stimulate Activity-Dependent CREB Pathway in the Deaf Auditory Cortex: Implications for Molecular Plasticity Induced by Neural Prosthetic Devices

Justin Tan1,2, Sandra Widjaja1, Jin Xu1 and Robert K. Shepherd1,2

1 The Bionic Ear Institute, East Melbourne, Victoria 3002, Australia, 2 Department of Otolaryngology, University of Melbourne, East Melbourne, Victoria 3002, Australia

Address correspondence to: Dr Justin Tan, Department of Otolaryngology, University of Melbourne, 32 Gisborne Street, East Melbourne, Victoria 3002, Australia. Email: jtan{at}bionicear.org.

Neural activity modulates the maturation of synapses and their organization into functional circuits by regulating activity-dependent signaling pathways. Phosphorylation of cyclic AMP/Ca2+-responsive element-binding protein (CREB) is widely accepted as a stimulus-inducible event driven by calcium influx into depolarized neurons. In turn, phosphorylated CREB (pCREB) activates the transcription of brain-derived neurotrophic factor (BDNF), which is needed for synaptic transmission and long-term potentiation. We examined how these molecular events are influenced by sensorineural hearing loss and long-term reactivation via cochlear implants. Sensorineural hearing loss reduced the expression of pCREB and BDNF. In contrast, deafened animals subject to long-term, unilateral intracochlear electrical stimulation exhibited an increased expression of pCREB and BDNF in the contralateral auditory cortical neurons, relative to ipsilateral ones. These changes induced by cochlear implants are further accompanied by the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which has been implicated in long-lasting forms of synaptic plasticity. Because CREB and BDNF are critical modulators of synaptic plasticity, our data describe for the first time possible molecular candidate genes, which are altered in the auditory cortex, following cochlear implantation. These findings provide insights into adaptive, molecular mechanisms recruited by the brain upon functional electrical stimulation by neural prosthetic devices.

Key Words: activity-dependent gene • BDNF • electrical stimulation • MAPK • sensorineural hearing loss • synaptic plasticity


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