Abstract
Animal models have demonstrated that tinnitus is a pathology of dysfunctional excitability in the central auditory system, in particular in the dorsal cochlear nucleus (DCN) of the brainstem. We used a murine model and studied whether acoustic over-exposure leading to hearing loss and tinnitus, affects long-term potentiation (LTP) at DCN multisensory synapses. Whole cell and field potential recordings were used to study the effects on release probability and synaptic plasticity, respectively in brainstem slices. Shifts in hearing threshold were quantified by auditory brainstem recordings, and gap-induced prepulse inhibition of the acoustic startle reflex was used as an index for tinnitus. An increased release probability that saturated LTP and thereby induced metaplasticity at DCN multisensory synapses, was observed 4–5days following acoustic over-exposure. Perfusion of an NMDA receptor antagonist or decreasing extracellular calcium concentration, decreased the release probability and restored LTP following acoustic over-exposure. In vivo administration of magnesium-threonate following acoustic over-exposure restored LTP at DCN multisensory synapses, and reduced gap detection deficits observed four months following acoustic over-exposure. These observations suggest that consequences of noise-induced metaplasticity could underlie the gap detection deficits that follow acoustic over-exposure, and that early therapeutic intervention could target metaplasticity and alleviate tinnitus.
Highlights
Tinnitus, the pathological percept of phantom sound, affects 10 to 15% of the adult population worldwide (Dawes et al, 2014; Shargorodsky et al, 2010)
We studied the modulation of long-term potentiation in brainstem slices containing the dorsal cochlear nucleus (DCN) by stimulating parallel fibers in the molecular layer and recording field potentials in the fusiform cell layer, as previously described in (Manis, 1989)
Subsequent high frequency stimulations failed to affect the paired pulse ratios. (C left) Absence of long-term potentiation (LTP) in presence of 10 μM this hypothesis using DLthreo-beta-benzyloxyaspartate (TBOA) (n = 5, N = 3; xr2 (2) = 2.8, NS, RM ANOVA on Ranks). (C right) Absence of paired pulse facilitation assessed at baseline stimulation rates in presence of 10 μM TBOA (n = 5, N = 3; xr2 (2) = 7.6, P = 0.01, RM ANOVA on Ranks)
Summary
The pathological percept of phantom sound, affects 10 to 15% of the adult population worldwide (Dawes et al, 2014; Shargorodsky et al, 2010). Acoustic overexposure triggering hearing loss and tinnitus has been shown to enhance DCN somatosensory and vestibular synaptic inputs (Barker et al, 2012; Shore et al, 2008) supporting the idea that tinnitus arises in response to enhanced multisensory synaptic transmission to the DCN (Shore et al, 2008). Whereas the presence of LTP has been demonstrated in the DCN (Tzounopoulos et al, 2004), direct evidence demonstrating metaplasticity in response to acoustic over-exposure triggering tinnitus has yet to be provided. We investigate the effect of acoustic over-exposure on plasticity at DCN multisensory synapses and a potential therapeutic reversal of this effect that ameliorates perception of tinnitus
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