Mechanisms contributing to central excitability changes during hearing loss

Pilati, Nadia; Ison, Matias J.; Barker, Matthew; Mulheran, M.; Large, Charles H.; Forsythe, Ian D.; Matthias, John; Hamann, Martine

doi:10.1073/pnas.1116981109

Cited by 51 publications

(59 citation statements)

References 64 publications

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“…Although our studies do not exclude other synaptic and intrinsic plasticity mechanisms that may contribute to the tinnitus-related changes in DCN excitability (18,58,59), our results highlight KCNQ2/3 channels as key players in the induction of tinnitus. KCNQ channels have been attractive targets for treating diseases associated with hyperexcitability (60); retigabine, a KCNQ channel activator, has been recently approved as an anticonvulsant.…”

Section: Plasticity Of Kcnq2/3 Channels Is Crucial For the Induction mentioning

confidence: 94%

Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus

Choi

Tzounopoulos

2013

Proc. Natl. Acad. Sci. U.S.A.

130

163

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Tinnitus, the perception of phantom sound, is often a debilitating condition that affects many millions of people. Little is known, however, about the molecules that participate in the induction of tinnitus. In brain slices containing the dorsal cochlear nucleus, we reveal a tinnitus-specific increase in the spontaneous firing rate of principal neurons (hyperactivity). This hyperactivity is observed only in noise-exposed mice that develop tinnitus and only in the dorsal cochlear nucleus regions that are sensitive to high frequency sounds. We show that a reduction in Kv7.2/3 channel activity is essential for tinnitus induction and for the tinnitus-specific hyperactivity. This reduction is due to a shift in the voltage dependence of Kv7 channel activation to more positive voltages. Our in vivo studies demonstrate that a pharmacological manipulation that shifts the voltage dependence of Kv7 to more negative voltages prevents the development of tinnitus. Together, our studies provide an important link between the biophysical properties of the Kv7 channel and the generation of tinnitus. Moreover, our findings point to previously unknown biological targets for designing therapeutic drugs that may prevent the development of tinnitus in humans.potassium channels | excitability | auditory brainstem | phantom perception T innitus is a common auditory disorder that is often the result of extreme sound exposure. An estimated 5-15% of the population experiences chronic tinnitus, with many millions of those sufferers disabled by this condition (1-3). With an even higher prevalence of chronic tinnitus in recent war veterans (4), the personal and financial costs of tinnitus have expanded dramatically. Despite the high prevalence of tinnitus, the neuronal mechanisms that mediate the initiation (induction) and the maintenance (expression) of the disorder remain poorly understood. As a result there is no generally accepted treatment, cure, or preventive method for tinnitus.Tinnitus is usually initiated by noise-induced cochlear damage that causes hair cell loss, ganglion cell degeneration, and reduced auditory nerve input to the central auditory system (5). Decreased peripheral input leads to pathogenic neuronal plasticity that results in subcortical hyperexcitability, increased neural synchrony, cortical reorganization, and ultimately stimulusindependent perception of sound (5-13). However, little is known about the plasticity mechanisms that initiate tinnitus. Elucidation of these mechanisms will lead to the development of drugs and therapies that can be applied soon after the acoustic trauma, thus preventing tinnitus from becoming permanent and irreversible.The dorsal cochlear nucleus (DCN) is an auditory brainstem nucleus that is indispensable to the induction of tinnitus: ablation of the DCN before noise exposure prevents the induction of tinnitus (14). Consistent with its key role in tinnitus generation, the DCN is a site where robust tinnitus-related neuronal plasticity has been identified (15). Studies in animal models of ...

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Section: Plasticity Of Kcnq2/3 Channels Is Crucial For the Induction mentioning

confidence: 94%

Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus

Choi

Tzounopoulos

2013

Proc. Natl. Acad. Sci. U.S.A.

130

163

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“…Stimulus timing-dependent frequency tuning suggests that STDP may be important for tonotopic remapping, which has been suggested as a correlate for tinnitus (Mühlnickel et al, 1998;Komiya and Eggermont, 2000). In other sensory systems, STDP is involved in elevated spontaneous activity and cortical remapping after sensory deprivation in visual (Guo et al, 2012) and somatosensory (Gambino and Holtmaat, 2012) cortices, respectively.…”

Section: Stdp Alterations As a Neural Correlate For Tinnitusmentioning

confidence: 99%

“…Alternatively, neuromodulatory systems may gate STDP (Pawlak et al, 2010). In DCN, cholinergic inputs modulate STDP at parallel fiber to fusiform cell synapses, converting it from Hebbian to anti-Hebbian (Zhao and Tzounopoulos, 2011).…”

Section: Potential Mechanisms Underlying Noise-induced Changes In Stimentioning

confidence: 99%

Stimulus Timing-Dependent Plasticity in Dorsal Cochlear Nucleus Is Altered in Tinnitus

2013

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Tinnitus and cochlear damage have been associated with changes in somatosensory-auditory integration and plasticity in the dorsal cochlear nucleus (DCN). Recently, we demonstrated in vivo that DCN bimodal plasticity is stimulus timing-dependent, with Hebbian and anti-Hebbian timing rules that reflect in vitro spike timing-dependent plasticity. In this in vivo study, we assessed the stimulus timing dependence of bimodal plasticity in a tinnitus model. Guinea pigs were exposed to a narrowband noise that produced a temporary elevation of auditory brainstem response thresholds. A total of 60% of the guinea pigs developed tinnitus as indicated by gap-induced prepulse inhibition of the acoustic startle. After noise exposure and tinnitus induction, stimulus timing-dependent plasticity was measured by comparing responses to sound before and after paired somatosensory and auditory stimulation presented with varying intervals and orders. In comparison with Sham and noise-exposed animals that did not develop tinnitus, timing rules in verified tinnitus animals were more likely to be anti-Hebbian and broader for those bimodal intervals in which the neural activity showed enhancement. Furthermore, units from exposed animals with tinnitus were more weakly suppressed than either Sham animals or exposed animals without tinnitus. The broadened timing rules in the enhancement phase in animals with tinnitus, and in the suppressive phase in exposed animals without tinnitus was in contrast to narrow, Hebbian-like timing rules in Sham animals. These findings implicate alterations in DCN bimodal spike timing-dependent plasticity as underlying mechanisms in tinnitus, opening the way for a therapeutic target.

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“…According to the hyperactivity model of tinnitus, neurons in the central auditory system respond to the weakened input of a sound-damaged cochlea by down-regulating inhibitory connections (Moller 2007;Middleton et al 2011;Wang et al 2011) and enhancing membrane excitability (Dong et al 2010;Pilati et al 2012;Koehler and Shore 2013;Li et al 2013). This "rebalancing" may raise spontaneous activity (i.e., activity in the absence of sound) to levels that impart a false perception of sound stimulation (Chen and Jastreboff 1995; Kaltenbach and Afman 2000;.…”

Section: Introductionmentioning

confidence: 99%

Effects of Unilateral Acoustic Trauma on Tinnitus-Related Spontaneous Activity in the Inferior Colliculus

Ropp

Tiedemann

Young

et al. 2014

JARO

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This study describes the long-term effects of soundinduced cochlear trauma on spontaneous discharge rates in the central nucleus of the inferior colliculus (ICC). As in previous studies, single-unit recordings in Sprague-Dawley rats revealed pervasive increases in spontaneous discharge rates. Based on differences in their sources of input, it was hypothesized that physiologically defined neural populations of the auditory midbrain would reveal the brainstem sources that dictate ICC hyperactivity. Abnormal spontaneous activity was restricted to target neurons of the ventral cochlear nucleus. Nearly identical patterns of hyperactivity were observed in the contralateral and ipsilateral ICC. The elevation in spontaneous activity extended to frequencies well below and above the region of maximum threshold shift. This lack of frequency organization suggests that ICC hyperactivity may be influenced by regions of the brainstem that are not tonotopically organized. Sound-induced hyperactivity is often observed in animals with behavioral signs of tinnitus. Prior to electrophysiological recording, rats were screened for tinnitus by measuring gap pre-pulse inhibition of the acoustic startle reflex (GPIASR). Rats with positive phenotypes did not exhibit unique patterns of ICC hyperactivity. This ambiguity raises concerns regarding animal behavioral models of tinnitus. If our screening procedures were valid, ICC hyperactivity is observed in animals without behavioral indications of the disorder. Alternatively, if the perception of tinnitus is strictly linked to ongoing ICC hyperactivity, our current behavioral approach failed to provide a reliable assessment of tinnitus state.

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Mechanisms contributing to central excitability changes during hearing loss

Cited by 51 publications

References 64 publications

Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus

Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus

Stimulus Timing-Dependent Plasticity in Dorsal Cochlear Nucleus Is Altered in Tinnitus

Effects of Unilateral Acoustic Trauma on Tinnitus-Related Spontaneous Activity in the Inferior Colliculus

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