Exposure to Sodium Salicylate Disrupts VGLUT3 Expression in Cochlear Inner Hair Cells and Contributes to Tinnitus

Abstract

To examine whether exposure to sodium salicylate disrupts expression of vesicular glutamate transporter 3 (VGLUT3) and whether the alteration in expression corresponds to increased risk for tinnitus. Rats were treated with saline (control) or sodium salicylate (treated) Rats were examined for tinnitus by monitoring gap-pre-pulse inhibition of the acoustic startle reflex (GPIAS). Auditory brainstem response (ABR) was applied to evaluate hearing function after treatment. Rats were sacrificed after injection to obtain the cochlea, cochlear nucleus (CN), and inferior colliculus (IC) for examination of VGLUT3 expression. No significant differences in hearing thresholds between groups were identified (p>0.05). Tinnitus in sodium salicylate-treated rats was confirmed by GPIAS. VGLUT3 encoded by solute carrier family 17 members 8 (SLC17a8) expression was significantly increased in inner hair cells (IHCs) of the cochlea in treated animals, compared with controls (p<0.01). No significant differences in VGLUT3 expression between groups were found for the cochlear nucleus (CN) or IC (p>0.05). Exposure to sodium salicylate may disrupt SLC17a8 expression in IHCs, leading to alterations that correspond to tinnitus in rats. However, the CN and IC are unaffected by exposure to sodium salicylate, suggesting that enhancement of VGLUT3 expression in IHCs may contribute to the pathogenesis of tinnitus.

Auditory Brainstem Responses (ABR) of Rats during Experimentally Induced Tinnitus: Literature Review

“…For the induction of tinnitus, three methods were used (Figure 3). In 14 articles, tinnitus was induced with salicylate [13,[27][28][29][49][50][51][52][53][58][59][60]66]. Nineteen reports analyzed tinnitus after noise exposure [15,44,45,[54][55][56][57][61][62][63][64][65][67][68][69][70][71] and three analyzed tinnitus after blast injury [46][47][48].…”

“…Different methods were used to determine if animals have tinnitus. In studies with substanceinduced tinnitus, the primary tinnitus-detection method was the gap-prepulse inhibition of the acoustic startle (GPIAS) [13,27,51,52,[58][59][60]. GPIAS is based on a hypothesis that assumes that the animals experiencing tinnitus have a fundamental deficit in hearing the silence.…”

“…In the articles selected for this review, Sprague-Dawley rats (both genders) were used in seventeen studies [13,28,[44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Wistar rats were used in thirteen [15,27,29,[58][59][60][61][62][63][64][65], Long-Evans rats were used in four [66][67][68][69], and Fischer rats (FBN) were used in three studies [49,70,71]. One research group used Fischer 344 and Sprague-Dawley rats [49], two studies used both female and male Wistar rats [29,60], and one article did not provide information about the age of rats [45].…”

“…In the studies using substance-induced tinnitus, the sample size varied from 4 to 69 animals. Remarkably, only seven of fourteen studies used a control group of animals [27,50,51,[58][59][60]66]. In studies using blast-and noise-induced tinnitus, the number of analyzed animals varied from three to 137.…”

Disruption of Glutamate Release and Uptake-Related Protein Expression After Noise-Induced Synaptopathy in the Cochlea

“…Within IHCs, Vglut3 facilitates the packaging of glutamate into vesicles which is subsequently secreted into the postsynaptic membrane during exocytosis, to transduce acoustic signals into neural signals. Disrupted expression or deletion of Vglut3 can lead to tinnitus ( Zhang W. et al, 2020 ) and deafness ( Ruel et al, 2008 ; Seal et al, 2008 ; Akil et al, 2012 ); previous studies have suggested that knocking out the Vglut3 allele results in decreased ribbon synapse density and the number of spiral ganglion nerves ( Kim et al, 2019 ). Moreover, ototoxic drugs ( Zhang Y. et al, 2020 ) and aging ( Peng et al, 2013 ) can also affect the expression of Vglut3.…”