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The alpha10 nicotinic acetylcholine receptor subunit is required for normal synaptic function and integrity of the olivocochlear system.

ABSTRACT: Although homomeric channels assembled from the alpha9 nicotinic acetylcholine receptor (nAChR) subunit are functional in vitro, electrophysiological, anatomical, and molecular data suggest that native cholinergic olivocochlear function is mediated via heteromeric nAChRs composed of both alpha9 and alpha10 subunits. To gain insight into alpha10 subunit function in vivo, we examined olivo cochlear innervation and function in alpha10 null-mutant mice. Electrophysiological recordings from postnatal (P) days P8-9 inner hair cells revealed ACh-gated currents in alpha10(+/+) and alpha10(+/-) mice, with no detectable responses to ACh in alpha10(-/-) mice. In contrast, a proportion of alpha10(-/-) outer hair cells showed small ACh-evoked currents. In alpha10(-/-) mutant mice, olivocochlear fiber stimulation failed to suppress distortion products, suggesting that the residual alpha9 homomeric nAChRs expressed by outer hair cells are unable to transduce efferent signals in vivo. Finally, alpha10(-/-) mice exhibit both an abnormal olivocochlear morphology and innervation to outer hair cells and a highly disorganized efferent innervation to the inner hair cell region. Our results demonstrate that alpha9(-/-) and alpha10(-/-) mice have overlapping but nonidentical phenotypes. Moreover, alpha10 nAChR subunits are required for normal olivocochlear activity because alpha9 homomeric nAChRs do not support maintenance of normal olivocochlear innervation or function in alpha10(-/-) mutant mice.

SUBMITTER: Vetter DE

PROVIDER: S-EPMC2154476 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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The alpha10 nicotinic acetylcholine receptor subunit is required for normal synaptic function and integrity of the olivocochlear system.

Vetter Douglas E DE Katz Eleonora E Maison Stéphane F SF Taranda Julián J Turcan Sevin S Ballestero Jimena J Liberman M Charles MC Elgoyhen A Belén AB Boulter Jim J

Proceedings of the National Academy of Sciences of the United States of America 20071212 51

Although homomeric channels assembled from the alpha9 nicotinic acetylcholine receptor (nAChR) subunit are functional in vitro, electrophysiological, anatomical, and molecular data suggest that native cholinergic olivocochlear function is mediated via heteromeric nAChRs composed of both alpha9 and alpha10 subunits. To gain insight into alpha10 subunit function in vivo, we examined olivo cochlear innervation and function in alpha10 null-mutant mice. Electrophysiological recordings from postnatal ...[more]

PMID: 18077337

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Project description:The presentation of nicotinic acetylcholine receptors (nAChRs) on synaptic membranes is crucial for generating cholinergic circuits, some of which are associated with memory function and neurodegenerative disorders. Although the physiology and structure of nAChR, a cation channel comprising five subunits, have been extensively studied, little is known about how the receptor levels in interneuronal synapses are determined and which nAChR subunits participate in the regulatory process in cooperation with synaptic cleft matrices and intracellular proteins. By a genetic screen of Drosophila, we identified mutations in the nAChR subunit Dα5 gene as suppressors that restored the mutant phenotypes of hig, which encodes a secretory matrix protein localized to cholinergic synaptic clefts in the brain. Only the loss of function of Dα5 among the 10 nAChR subunits suppressed hig mutant phenotypes in both male and female flies. Dα5 behaved as a lethal factor when Hig was defective; loss of Dα5 in hig mutants rescued lethality, upregulating Dα6 synaptic levels. By contrast, levels of Dα5, Dα6, and Dα7 subunits were all reduced in hig mutants. These three subunits have distinct properties for interaction with Hig or trafficking, as confirmed by chimeric subunit experiments. Notably, the chimeric Dα5 protein, which has the extracellular sequences that display no positive interaction with Hig, exhibited abnormal distribution and lethality even in the presence of Hig. We propose that the sequestering subunit Dα5 functions by reducing synaptic levels of nAChR through internalization, and this process is blocked by Hig, which tethers Dα5 to the synaptic cleft matrix.SIGNIFICANCE STATEMENT Because the cholinergic synapse is one of the major synapses that generate various brain functions, numerous studies have sought to reveal the physiology and structure of the nicotinic acetylcholine receptor (nAChR). However, little is known about how synaptic levels of nAChR are controlled and which nAChR subunits participate in the regulatory process in cooperation with synaptic cleft matrices. By a genetic screen of Drosophila, we identified mutations in the nAChR subunit Dα5 gene as suppressors that restored the mutant phenotypes of hig, which encodes a secretory matrix protein localized to cholinergic synaptic clefts. Our data indicate that Dα5 functions in reducing synaptic levels of nAChR, and this process is blocked by Hig, which tethers Dα5 to the synaptic cleft matrix.

Dataset Information

The alpha10 nicotinic acetylcholine receptor subunit is required for normal synaptic function and integrity of the olivocochlear system.

Publications

The alpha10 nicotinic acetylcholine receptor subunit is required for normal synaptic function and integrity of the olivocochlear system.

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