GLAST Deficiency in Mice Exacerbates Gap Detection Deficits in a Model of Salicylate-Induced Tinnitus

Abstract

Gap detection or gap pre-pulse inhibition of the acoustic startle (GPIAS) has been successfully used in rat and guinea pig models of tinnitus, yet this system has been proven to have low efficacy in CBA mice, with low basal GPIAS and subtle tinnitus-like effects. Here, we tested five mouse strains (CBA, BalbC, CD-1, C57BL/6 and 129sv) for pre-pulse inhibition (PPI) and gap detection with varying interstimulus intervals (ISI) and found that mice from a CBA genetic background had the poorest capacities of suppressing the startle response in the presence of a pre-pulse or a gap. CD-1 mice displayed variable responses throughout all ISI. Interestingly, C57BL/6, 129sv and BalbC showed efficient suppression with either pre-pulses or gaps with shorter ISI. The glutamate aspartate transporter (GLAST) is expressed in support cells from the cochlea and buffers the excess of glutamate. We hypothesized that loss of GLAST function could sensitize the ear to tinnitus-inducing agents, such as salicylate. Using shorter ISI to obtain a greater dynamic range to assess tinnitus-like effects, we found that disruption of gap detection by salicylate was exacerbated across various intensities of a 32-kHz narrow band noise gap carrier in GLAST knockout (KO) mice when compared to their wild-type (WT) littermates. Auditory brainstem responses (ABR) and distortion-product otoacoustic emission (DPOAE) were performed to evaluate the effects on hearing functions. Salicylate caused greater auditory threshold shifts (near 15 dB) in GLAST KO mice than in WT mice across all tested frequencies, despite similarly reduced DPOAE. Despite these changes, inhibition using broad-band gap carriers and 32 kHz pre-pulses were not affected. Our study suggests that GLAST deficiency could become a useful experimental model to decipher the mechanisms underlying drug-induced tinnitus. Future studies addressing the neurological correlates of tinnitus in this model could provide additional insights into the mechanisms of tinnitus.

Circadian vulnerability of cisplatin‐induced ototoxicity in the cochlea

“…GLAST KO mice 31 and their WT littermates were obtained from heterozygous (HET) crosses or from KO males crossed with HET females. Similar to what we previously reported, 24 we observed a non-mendelian distribution in the progeny of crosses between heterozygous KO mice (n = 200): 29% wild-type animals, 54% heterozygous knockout animals, and 15% homozygous knockout animals. Two percent of the pups had an unclear genotype.…”

“…Cochlear frequency mapping was then performed using a custom plug-in to ImageJ from NIH (Measure_Line.class from the Liberman laboratory at the Eaton-Peabody Laboratory). This gave the total length of the cochlea and their respective frequency points and was used as a guide obtaining confocal images for discrete frequency regions (6,8,12,16,24,32,48, and 64 kHz) along the length of the cochlea. Confocal z-stacks , with dimensions 1024 × 1024 and 16-bit image, along discrete regions of the basilar membrane were made with a 63× oil immersion objective (NA1.40) on a Zeiss LSM 880 confocal microscope.…”

“…21 Consistently, mice lacking GLAST show greater hearing threshold shifts and synaptic damage than do wild-type (WT) mice after noise exposure, 22 as well as greater vulnerability to aminoglycoside and salicylate ototoxicity. 23,24 As guinea pigs and rats are more susceptible than mice to cisplatin-mediated ototoxicity, 25 GLAST may potentially be involved in the protection of the synapse subjected to cisplatin treatment. Furthermore, since humans do not display GLAST expression in IPCs, 26 GLAST KO mice may more closely reflect the vulnerability of the human synapse to auditory insults, and thus, facilitate the translation of preclinical findings to humans.…”

Biomarkers of Presbycusis and Tinnitus in a Portuguese Older Population

“…Interestingly, neonatal exposure to monosodium glutamate has been shown to induce neuronal atrophy and dysmorphia in the cochlear nucleus and in the superior olivary complex ( Foran et al, 2017 ). The physiological effects of glutamate excitotoxicity therefore are concluded to include ARHL ( Pujol et al, 1993 ) and tinnitus ( Brozoski et al, 2012 ; Sahley et al, 2013 ; Yu et al, 2016 ).…”

Divergent Responses in the Gap Prepulse Inhibition of the Acoustic Startle Reflex in Two Different Guinea Pig Colonies

“…Studies have shown that GPIAS can be used in rats 8,15,16 , mice [17][18][19][20] and guinea pigs 11,21,22 . In addition, it has been used after a variety of tinnitus-inducing methods such as after salicylate or quinine 15,23 as well as after acoustic overexposure 16 . Specific parameters, such as the frequency of the background noise and intensity of the startle stimuli used by the different research groups, vary dependent on the natural audiograms of the species used and on the method used to induce tinnitus 15,16,24 .…”