GABAergic neural activity involved in salicylate-induced auditory cortex gain enhancement

Abstract

Although high doses of sodium salicylate impair cochlear function, it paradoxically enhances sound-evoked activity in the auditory cortex (AC) and augments acoustic startle reflex responses, neural and behavioral metrics associated with hyperexcitability and hyperacusis. To explore the neural mechanisms underlying salicylate-induced hyperexcitability and “increased central gain”, we examined the effects of γ-aminobutyric acid (GABA) receptor agonists and antagonists on salicylate-induced hyperexcitability in the AC and startle reflex responses. Consistent with our previous findings, local or systemic application of salicylate significantly increased the amplitude of sound-evoked AC neural activity, but generally reduced spontaneous activity in the AC. Systemic injection of salicylate also significantly increased the acoustic startle reflex. S-baclofen or R-baclofen, GABA-B agonists, which suppressed sound-evoked AC neural firing rate and local field potentials, also suppressed the salicylate-induced enhancement of the AC field potential and the acoustic startle reflex. Local application of vigabatrin, which enhances GABA concentration in the brain, suppressed the salicylate-induced enhancement of AC firing rate. Systemic injection of vigabatrin also reduced the salicylate-induced enhancement of acoustic startle reflex. Collectively, these results suggest that the sound-evoked behavioral and neural hyperactivity induced by salicylate may arise from a salicylate-induced suppression GABAergic inhibition in the AC.

Salicylate-induced cochlear impairments, cortical hyperactivity and re-tuning, and tinnitus

“…Because high doses of the drug reliably induce tinnitus, SS has been widely used to study the perceptual, anatomical, behavioral and neurophysiological aspects of tinnitus in animal models (Jastreboff et al, 1988b; McFadden et al, 1984a; Ochi and Eggermont, 1996; Wallhausser-Franke et al, 2003). While salicylate and aspirin have long been known to impair cochlear function (Stypulkowski, 1990), more recent studies indicate that it affects many different parts of the central nervous system (CNS) (Bauer et al, 2000; Gong et al, 2008; Lu et al, 2011; Mahlke and Wallhausser-Franke, 2004; Panford-Walsh et al, 2008; Sun et al, 2009). Paradoxically, the functional impairments seen in the CNS differ in several important ways from those seen in the cochlea.…”

“…In the auditory periphery, SS depresses cochlear sensitivity by reducing outer hair cell (OHC) electromotility (Kakehata and Santos-Sacchi, 1996; Tunstall et al, 1995) and decreases the neural output of the cochlea. In contrast, systemic treatment with a high-dose SS causes the auditory cortex (AC) to become hyperactive in response to high-level sound stimulation (Lu et al, 2011; Sun et al, 2009; Yang et al, 2007). These changes may be related to altered γ-aminobutyric acid (GABA) and serotonin mediated neurotransmission in the CNS (Bauer et al, 2000; Caperton and Thompson, 2011; Gong et al, 2008; Liu et al, 2003; Lu et al, 2011; Xu et al, 2005).…”

“…In contrast, systemic treatment with a high-dose SS causes the auditory cortex (AC) to become hyperactive in response to high-level sound stimulation (Lu et al, 2011; Sun et al, 2009; Yang et al, 2007). These changes may be related to altered γ-aminobutyric acid (GABA) and serotonin mediated neurotransmission in the CNS (Bauer et al, 2000; Caperton and Thompson, 2011; Gong et al, 2008; Liu et al, 2003; Lu et al, 2011; Xu et al, 2005). In addition, high-dose SS increased expression of c-fos , an activity-dependent protein, in the AC, as well as several non-classical auditory regions (e.g., amygdala) associated with stress, anxiety and emotion (Wallhausser-Franke et al, 2003).…”

Altered intensity coding in the salicylate-overdose animal model of tinnitus

“…In previous studies on auditory cortical response in tinnitus models, the response metric used was typically the peak amplitude (Lu et al, 2011;Sun et al, 2009;Stolzberg et al, 2012a). This measurement requires not only a good signal to noise ratio in the evoked waveform, but also clear peaks and valleys.…”

“…Symptoms of this disorder, besides some degree of hearing loss, include: (a) the perception of phantom sound (i.e., in clinical terms, tinnitus); and/or (b) the overly-loud perception of sounds at moderate levels (i.e., in clinical terms, hyperacusis) (Baguley, 2003;Wang et al, 2008). May or may not be related to hyperacusis, a number of electrophysiological recordings from auditory cortex in awake rats showed enhanced responses during experimental tinnitus (e.g., with salicylate overdose or acoustic trauma) (Eggermont, 2013;Lu et al, 2011;Sun et al, 2009;Stolzberg et al, 2012a,b). No effective cure, but only behavioral management is available to treat tinnitus as the underlying pathophysiology still remains unclear (Cazals, 2000;Jastreboff, 2007;Møller, 2007).…”