期刊
HUMAN MOLECULAR GENETICS
卷 27, 期 5, 页码 860-874出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddy007
关键词
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资金
- Research Training Group Molecular Basis of Sensory Biology [GRK 1885/1]
- DFG cluster of Excellence [EXC 1077/1]
- Israel Science Foundation [1320/11]
- Israeli Centers of Research Excellence (I-CORE) [41/11]
- Wellcome Trust [100699]
- Medical Research Council [G0300212]
- EC [CT-97-2715]
- Biotechnology and Biological Sciences Research Council [BB/M02069X/1] Funding Source: researchfish
- Medical Research Council [MR/N012119/1, MC_qA137918] Funding Source: researchfish
- BBSRC [BB/M02069X/1] Funding Source: UKRI
- MRC [G0300212, MR/N012119/1, MC_qA137918] Funding Source: UKRI
The peripheral deafness gene Mir96 is expressed in both the cochlea and central auditory circuits. To investigate whether it plays a role in the auditory system beyond the cochlea, we characterized homozygous Dmdo/Dmdo mice with a point mutation in miR-96. Anatomical analysis demonstrated a significant decrease in volume of auditory nuclei in Dmdo/Dmdo mice. This decrease resulted from decreased cell size. Non-auditory structures in the brainstem of Dmdo/Dmdo mice or auditory nuclei of the congenital deaf Cldn14(-/-) mice revealed no such differences. Electrophysiological analysis in the medial nucleus of the trapezoid body (MNTB) showed that principal neurons fired preferentially multiple action potentials upon depolarization, in contrast to the single firing pattern prevalent in controls and Cldn14(-/-) mice. Immunohistochemistry identified significantly reduced expression of two predicted targets of the mutated miR-96, K(v)1.6 and BK channel proteins, possibly contributing to the electrophysiological phenotype. Microscopic analysis of the Dmdo/Dmdo calyx of Held revealed a largely absent compartmentalized morphology, as judged by SV2-labeling. Furthermore, MNTB neurons from Dmdo/Dmdo mice displayed larger synaptic short-term depression, slower AMPA-receptor decay kinetics and a larger NMDA-receptor component, reflecting a less matured stage. Again, these synaptic differences were not present between controls and Cldn14(-/-) mice. Thus, deafness genes differentially affect the auditory brainstem. Furthermore, our study identifies miR-96 as an essential gene regulatory network element of the auditory system which is required for functional maturation in the peripheral and central auditory system alike.
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