Abstract
BackgroundIt has previously been shown that deletion of chrna9, the gene encoding the α9 nicotinic acetylcholine receptor (nAChR) subunit, results in abnormal synaptic terminal structure. Additionally, all nAChR-mediated cochlear activity is lost, as characterized by a failure of the descending efferent system to suppress cochlear responses to sound. In an effort to characterize the molecular mechanisms underlying the structural and functional consequences following loss of α9 subunit expression, we performed whole-transcriptome gene expression analyses on cochleae of wild type and α9 knockout (α9−/−) mice during postnatal days spanning critical periods of synapse formation and maturation.Principal FindingsData revealed that loss of α9 receptor subunit expression leads to an up-regulation of genes involved in synaptic transmission and ion channel activity. Unexpectedly, loss of α9 receptor subunit expression also resulted in an increased expression of genes encoding GABA receptor subunits and the GABA synthetic enzyme, glutamic acid decarboxylase. These data suggest the existence of a previously unrecognized association between the nicotinic cholinergic and GABAergic systems in the cochlea. Computational analyses have highlighted differential expression of several gene sets upon loss of nicotinic cholinergic activity in the cochlea. Time-series analysis of whole transcriptome patterns, represented as self-organizing maps, revealed a disparate pattern of gene expression between α9−/− and wild type cochleae at the onset of hearing (P13), with knockout samples resembling immature postnatal ages.ConclusionsWe have taken a systems biology approach to provide insight into molecular programs influenced by the loss of nicotinic receptor-based cholinergic activity in the cochlea and to identify candidate genes that may be involved in nicotinic cholinergic synapse formation, stabilization or function within the inner ear. Additionally, our data indicate a change in the GABAergic system upon loss of α9 nicotinic receptor subunit within the cochlea.
Highlights
In the mature mammalian cochlea, auditory stimuli are transduced into receptor potentials and transmitted to the brain via cochlear inner hair cells (IHCs) and the ganglion cells contacting them
We defined individual genes that have undergone differential expression across age and genotype. This was followed by an analysis of our data at the level of gene sets in an attempt to discern potentially novel gene interactions that are impacted by loss of nicotinic acetylcholine receptor (nAChR) activity
This was followed by a dynamic analysis of the whole transcriptome to decrease the high dimensionality of the data and annotate coordinated genome wide responses that occur over age and by genotype
Summary
In the mature mammalian cochlea, auditory stimuli are transduced into receptor potentials and transmitted to the brain via cochlear inner hair cells (IHCs) and the ganglion cells contacting them. The acetylcholine sensitivity of this synapse is generated by a heteromeric nicotinic receptor composed of two subunits, a9 and a10 [4,5], arranged in a pentameric structure [6]. A recent study of postnatal development of the cochlea has provided clues that loss of nAChR activity has consequences to the expression of a wide array of proteins potentially involved in synapse maturation [13]. In an effort to characterize the molecular mechanisms underlying the structural and functional consequences following loss of a9 subunit expression, we performed whole-transcriptome gene expression analyses on cochleae of wild type and a9 knockout (a92/2) mice during postnatal days spanning critical periods of synapse formation and maturation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
