Elsevier

Neuroscience Letters

Volume 586, 23 January 2015, Pages 60-64
Neuroscience Letters

Short communication
Glutamic acid decarboxylase levels in the cochlear nucleus of rats with acoustic trauma-induced chronic tinnitus

https://doi.org/10.1016/j.neulet.2014.11.047Get rights and content

Highlights

  • Tinnitus is associated with neuronal hyperactivity in the cochlear nucleus.

  • This could be due to a reduction in glutamic acid decarboxylase.

  • We tested this in rats at 22 weeks following acoustic trauma.

  • We found no evidence of a significant change in glutamic acid decarboxylase.

  • Chronic tinnitus may not be associated with long term changes in this enzyme.

Abstract

Tinnitus is the perception of phantom sounds, a phenomenon believed to be due to abnormal neuronal activity in auditory regions of the CNS such as the brainstem cochlear nucleus (CN). One possible mechanism for the abnormal neuronal activity in the CN, supported by recent animal studies, is a decrease in GABAergic inhibition. One possible explanation for this is a decrease in the enzyme responsible for the synthesis of GABA, glutamic acid decarboxylase (GAD). In this study, we used immunohistochemistry to analyse the levels of GAD in the dorsal and ventral CN of rats that had been exposed to noise trauma and had been confirmed to exhibit psychophysical evidence of tinnitus (at 17.5 weeks post-exposure) using a conditioned behavioural task. At 22 weeks following noise trauma or sham treatment, the levels of GAD in the dorsal and ventral CN were not significantly different. This result suggests that acoustic trauma that can cause chronic tinnitus is not associated with changes in GAD in the CN at 22 weeks post-exposure.

Introduction

Tinnitus is the perception of phantom sound, often described as a “ringing in the ears” [2]. Although many people experience tinnitus transiently, it can also become a chronic condition that has a severe negative impact on the quality of life. Symptoms of tinnitus persisting beyond a 6 month period define it as a chronic condition, and approximately 10–15% of the population is affected, requiring medical intervention [9], [10]. Aging, exposure to loud noise and certain drugs have the potential to cause auditory damage and tinnitus, and there is an urgent need for a more standardised clinical management and effective therapies [10]. However, a prerequisite for more effective treatment is a better understanding of the pathophysiology of the condition.

Increased spontaneous activity and tonotopic map reorganisation in the auditory brain regions have been correlated with tinnitus, yet the mechanisms underlying these changes are not well understood [2]. One of the hypotheses is that a down-regulation of inhibitory neurotransmission might be responsible for the neuronal hyperactivity and tinnitus generation [13], [15]. This was supported by evidence that pharmacological manipulations enhancing brain GABAergic transmission reduced behavioural signs of tinnitus in animals [6], [16], [20]. It has been shown that a hearing loss-induced decrease in inhibitory synaptic transmission occurs in the auditory cortical area corresponding to the tinnitus frequency and this decrease in inhibitory synaptic transmission is also correlated with a reduced level of glutamic acid decarboxylase (GAD), the enzyme responsible for the synthesis of GABA, in the same area [16]. Time-dependent changes in GAD levels following acoustic trauma have also been reported in the rat inferior colliculus (IC) [12]. In addition, evidence of reduced GABAergic inhibition and increased spontaneous activity has also been found in the dorsal cochlear nucleus (DCN) of mice with behaviour signs of tinnitus [11]. Since the CN is the first region of the CNS to receive and process auditory information, it occupies an pivotal role in the generation of tinnitus [3]. The dorsal cochlear nucleus (DCN), especially, has been proposed as a tinnitus trigger site [7]. Therefore, changes in GABAergic inhibition in the DCN would alter the balance of excitation and inhibition, resulting in disruption of responses in the higher auditory pathways [11]. The aim of this study, therefore, was to further investigate tinnitus-related long-term changes in GABAergic inhibition in the CN by comparing the expression of GAD in rats exposed to acoustic trauma that induced tinnitus with that in rats that were not exposed to acoustic trauma, using immunohistochemistry. In addition, GAD expression was also compared between rats that received l-baclofen, a GABAB receptor agonist and those that did not, in order to test the hypothesis that increasing GABAergic inhibition by administering l-baclofen alters GAD levels associated with tinnitus.

Section snippets

Experimental design

Data were obtained from the brains of 20 male Wistar rats (200–300 g) that were part of a larger study investigating the effects of l-baclofen on tinnitus perception [19]. In the original study, the animals were divided into several groups: exposed (acoustic trauma) + vehicle, sham control + vehicle, exposed-baclofen and sham-baclofen with n = 8 in each group [19]. For the purpose of this study, i.e. to investigate tinnitus-related changes in GAD levels, only the brains from animals with confirmed

Results

There was a significant elevation of ABR thresholds immediately after noise exposure (F(1, 47.14) = 62.99, P  0.001; see Fig. 1A and B in [19]); however, the ABR thresholds had returned to normal by 22 weeks when they were measured prior to sacrifice (see Fig. 1C in [19]). At 2 weeks after the acoustic trauma and the first vehicle or drug treatment, the animals were tested in the conditioned behavioural paradigm for indications of tinnitus [19]. In response to either broad band noise (BBN) or 32 

Discussion

The results of this study showed that there was no significant difference between the intensity of GAD immunolabelling in the VCN or DCN of exposed rats confirmed to have tinnitus at 17.5 weeks following exposure, compared to sham rats, when the DCN and VCN were analysed at 22 weeks post-exposure. There was also no difference between the rats treated with l-baclofen and vehicle. This result suggests that GAD levels in the CN are not altered at 22 weeks post-exposure or correlated with the

Acknowledgements

This research was supported by grants from the Jean Cathie Estate and the New Zealand Neurological Foundation. KM was supported by a University of Otago MSc Scholarship and SD by a Beswick Summer Scholarship.

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