Abstract
Noise overexposure may induce permanent noise-induced hearing loss (NIHL). The cochlear nucleus complex (CNC) is the entry point for sensory information in the central auditory system. Impairments in gamma-aminobutyric acid (GABA)—mediated synaptic transmission in the CNC have been implicated in the pathogenesis of auditory disorders. However, the role of protein kinase C (PKC) signaling pathway in GABAergic inhibition in the CNC in NIHL remains elusive. Thus, we investigated the alterations of glutamic acid decarboxylase 67 (GAD67, the chemical marker for GABA-containing neurons), PKC γ subunit (PKCγ) and GABAB receptor (GABABR) expression in the CNC using transgenic GAD67-green fluorescent protein (GFP) knock-in mice, BALB/c mice and C57 mice. Immunohistochemical results indicate that the GFP-labeled GABAergic neurons were distributed in the molecular layer (ML) and fusiform cell layer (FCL) of the dorsal cochlear nucleus (DCN). We found that 69.91% of the GFP-positive neurons in the DCN were immunopositive for both PKCγ and GABABR1. The GAD67-positive terminals made contacts with PKCγ/GABABR1 colocalized neurons. Then we measured the changes of auditory thresholds in mice after noise exposure for 2 weeks, and detected the GAD67, PKCγ, and GABABR expression at mRNA and protein levels in the CNC. With noise over-exposure, there was a reduction in GABABR accompanied by an increase in PKCγ expression, but no significant change in GAD67 expression. In summary, our results demonstrate that alterations in the expression of PKCγ and GABABRs may be involved in impairments in GABAergic inhibition within the CNC and the development of NIHL.
Highlights
Human exposure to excessive noise has been linked to noiseinduced hearing loss (NIHL) (Chung et al, 2005)
Because of the limited ability to identify the GABAergic neurons in brainstem with the use of antibodies against gamma-aminobutyric acid (GABA) or glutamic acid decarboxylases (GAD) (Sloviter and Nilaver, 1987; Sloviter et al, 2001) and GAD67 is responsible for over 90% of basal GABA synthesis in brain, we revealed the localization of GABAergic neurons in the cochlear nucleus complex (CNC) by employing the GAD67-green fluorescent protein (GFP) knock-in mice, in which the GAD67 mRNA is colocalized with GFP, and GFP is expressed in GABAergic neurons (Tamamaki et al, 2003; Huang et al, 2008; Han et al, 2010)
IMMUNOHISTOCHEMICAL DETECTION OF GFP, GAD67, GABABR1s, AND PKC γ subunit (PKCγ) IN THE CNC Our studies indicate the localization of GABAergic neurons in the CNC by employing the GAD67-GFP knock-in mouse, in which GFP is expressed in GABAergic neurons (Tamamaki et al, 2003; Li et al, 2005; Huang et al, 2008; Huo et al, 2009; Han et al, 2010)
Summary
Human exposure to excessive noise has been linked to noiseinduced hearing loss (NIHL) (Chung et al, 2005). Recent studies have suggested that noise overexposure potentially results in auditory threshold shifts in young adult animals via a series of neuroplastic changes in central auditory structures (Fritschy et al, 2008; Wang et al, 2009a). The cochlear nucleus complex (CNC) occupies a pivotal position in the hierarchy of functional processes leading to convergence of auditory information. The CNC can be divided into the dorsal cochlear nucleus (DCN) and the ventral cochlear nucleus (VCN). The DCN receives peripheral afferents and sets up processing pathways into the inferior colliculus (IC). The DCN forms a layered structure: the molecular layer (ML), the fusiform cell layer (FCL), and the deep layer (DL) (Osen, 1969)
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