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Protein expression pattern in cerebellum of Cav2.1 mutant, tottering-6j mice.

ABSTRACT: Neuronal voltage-gated Cav2.1 channel controls a broad array of functions, including neurotransmitter release, neuronal excitability, activity-dependent gene expression, and neuronal survival. The Cav2.1 channel is molecular complexes consisting of several subunits: ?1, ?2/?, ?, and ?. The pore-forming subunit, ?1, is encoded by the Cacna1a gene. Tottering-6j mice, generated by the Neuroscience Mutagenesis Facility at The Jackson Laboratory, are a recessive mutant strain in which the mutation has been chemically induced by ethylnitrosourea. In tottering-6j mice, mutation in the Cacna1a gene results in a base substitution (C-to-A) in the consensus splice acceptor sequence, which results in deletion of a part of the S4-S5 linker, S5, and a part of S5-S6 linker domain I in the ?1 subunit of Cav2.1 channel. The mice display motor dysfunctions and absence-like seizures. However, protein expression in the cerebellum of tottering-6j mice has not been investigated. Real-time quantitative reverse transcription polymerase chain reaction and histological analyses of the cerebellum of tottering-6j mice revealed high expression levels of tyrosine hydroxylase, zebrin II, and ryanodine receptor 3 compared with those of wild-type mice. Conversely, a low level of calretinin expression was found compared with wild-type mice. These results indicate that Cacna1a mutation plays a significant role in protein expression patterns and that the tottering-6j mouse is a useful model for understanding protein expression mechanisms.

SUBMITTER: Kim TY

PROVIDER: S-EPMC4976234 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Protein expression pattern in cerebellum of Cav2.1 mutant, tottering-6j mice.

Kim Tae Yeon TY Niimi Kimie K Takahashi Eiki E

Experimental animals 20160217 3

Neuronal voltage-gated Cav2.1 channel controls a broad array of functions, including neurotransmitter release, neuronal excitability, activity-dependent gene expression, and neuronal survival. The Cav2.1 channel is molecular complexes consisting of several subunits: α1, α2/δ, β, and γ. The pore-forming subunit, α1, is encoded by the Cacna1a gene. Tottering-6j mice, generated by the Neuroscience Mutagenesis Facility at The Jackson Laboratory, are a recessive mutant strain in which the mutation ha ...[more]

PMID: 26887908

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Project description:It is widely accepted that even a single acute noise exposure at moderate intensity that induces temporary threshold shift (TTS) can result in permanent loss of ribbon synapses between inner hair cells and afferents. However, effects of repeated or chronic noise exposures on the cochlear synapses especially medial olivocochlear (MOC) efferent synapses remain elusive. Based on a weeklong repeated exposure model of bandwidth noise over 2-20 kHz for 2 hours at seven intensities (88 to 106 dB SPL with 3 dB increment per gradient) on C57BL/6J mice, we attempted to explore the dose-response mechanism of prolonged noise-induced audiological dysfunction and cochlear synaptic degeneration. In our results, mice repeatedly exposed to relatively low-intensity noise (88, 91, and 94 dB SPL) showed few changes on auditory brainstem response (ABR), ribbon synapses, or MOC efferent synapses. Notably, repeated moderate-intensity noise exposures (97 and 100 dB SPL) not only caused hearing threshold shifts and the inner hair cell ribbon synaptopathy but also impaired MOC efferent synapses, which might contribute to complex patterns of damages on cochlear function and morphology. However, repeated high-intensity (103 and 106 dB SPL) noise exposures induced PTSs mainly accompanied by damages on cochlear amplifier function of outer hair cells and the inner hair cell ribbon synaptopathy, rather than the MOC efferent synaptic degeneration. Moreover, we observed a frequency-dependent vulnerability of the repeated acoustic trauma-induced cochlear synaptic degeneration. This study provides a sight into the hypothesis that noise-induced cochlear synaptic degeneration involves both afferent (ribbon synapses) and efferent (MOC terminals) pathology. The pattern of dose-dependent pathological changes induced by repeated noise exposure at various intensities provides a possible explanation for the complicated cochlear synaptic degeneration in humans. The underlying mechanisms remain to be studied in the future.

Dataset Information

Protein expression pattern in cerebellum of Cav2.1 mutant, tottering-6j mice.

Publications

Protein expression pattern in cerebellum of Cav2.1 mutant, tottering-6j mice.

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