Enhancement of Endocannabinoid-dependent Depolarization-induced Suppression of Excitation in Glycinergic Neurons by Prolonged Exposure to High Doses of Salicylate

Zugaib, João; Leão, Ricardo M.

doi:10.1016/j.neuroscience.2018.02.016

Cited by 12 publications

(10 citation statements)

References 48 publications

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“…Excitatory-inhibitory imbalances and synaptic dysfunction lead to neurological and psychiatric disorders (47,48). The latest discovery of Zugaib et al (49) demonstrated endocannabinoid-dependent depolarization-induced suppression of excitation in glycinergic neurons were enhanced as mice were exposed to prolonged high doses of salicylate. The results pointed to an increased inhibition of the dorsal cochlear nucleus (DCN) inhibitory cartwheel neuron during depolarizations, which is potentially significant for DCN hyperactivity and tinnitus generation.…”

Section: Discussionmentioning

confidence: 99%

Long‑term treatment with salicylate enables NMDA receptors and impairs AMPA receptors in C57BL/6J mice inner hair cell ribbon synapse

et al. 2018

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Salicylate is widely used to produce animal models of tinnitus in mice and/or rats. The side effects on auditory function, including hearing loss and tinnitus, are considered the results of the auditory nerve dysfunction. A recent study indicated that chronic treatment with salicylate for several weeks reduces compressed action potential amplitude, which is contradictory to the studies reporting excessive activation of N-methyl-D-aspartate receptors (NMDAR) in tinnitus-induced animals. The specific aims of the experiment were to detect the effect of salicylate on the inner hair cells (IHCs), ribbon synapse, as well as the association between the hearing threshold and the number of mismatched ribbon synapses. In the present study, mice were injected intraperitoneally with a low dose of salicylate (200 mg/kg) for 14 days. The auditory brainstem response and otoacoustic emission were measured to assess auditory function of the mice. The postsynaptic regions of IHC were identified with two types of immunostaining targets: Postsynaptic density protein 95 and Glu2/3. The number of spheres was counted and the synapses were reconstructed in 3-dimensional images. Increases in distortion product otoacoustic emissions amplitudes of the salicylate group were detected, however, an elevation in the hearing threshold was also observed. A mismatch between pre-and post-ribbon synapses was observed. In addition, the cochlear components, including the numbers of outer hair cells and IHCs, were unlikely to be affected by salicylate. IHC ribbon synapses were more susceptible to salicylate stimuli. Furthermore, mismatch of pre- and post-ribbon synapses may indicate a competitive inhibition between NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxa-zole-propionate receptors and dysfunction of ribbon synapses.

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Section: Discussionmentioning

confidence: 99%

Long‑term treatment with salicylate enables NMDA receptors and impairs AMPA receptors in C57BL/6J mice inner hair cell ribbon synapse

et al. 2018

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“…Our motivation for this research was to investigate the ionic mechanisms underlying the quiet and active states of CW neurons from the DCN. Because of its central role in the inhibition of the fusiform neuron, knowing the ionic channels controlling the firing of the glycinergic CW cell is central to understand the mechanisms of the hyperexcitability observed in the fusiform neuron in animal models of tinnitus (Kaltenbach and Afman., 2000;Brozoski et al, 2002), which can be related to a decrease in the glycinergic inhibition from CW neurons (Zugaib et al, 2016, Zugaib andLeão, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is possible that salicylate acts by decreasing ATP levels near KATP channels or activating AMPK. Moreover, high doses of salicylate potentiate the depolarizationinduced suppression of excitation (DSE) on the excitatory synapses on the CW neurons (Zugaib and Leão, 2018), and, interestingly, activation of AMPK has been shown to potentiate DSE on hypothalamic neurons (Borgquist et al, 2015). The effects of salicylate on the cartwheel neuron can have a profound impact on the excitability of the fusiform neurons, and KATP channel regulation may be one important factor contributing to the development of tinnitus by this drug.…”

Section: Discussionmentioning

confidence: 99%

ATP-sensitive K⁺channels control the spontaneous firing of a glycinergic interneuron in the auditory brainstem

Strazza

Siqueira

Benites

et al. 2020

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Cartwheel neurons from the dorsal cochlear nucleus (DCN) are glycinergic interneurons and the primary source of inhibition on the fusiform neurons, the principal excitatory neuron in the DCN. Most cartwheel neurons present spontaneous firing (active neurons), producing a steady inhibitory tone on fusiform neurons. In contrast, a smaller fraction does not fire spontaneously (quiet neurons). Additionally, hyperactivity of fusiform neurons is seen in animals with behavioral evidence of tinnitus. Due to its relevance in controlling the excitability of fusiform neurons, we investigated the ion channels responsible for the spontaneous firing of cartwheel neurons. We found that quiet neurons express an outward conductance not seen in active neurons, which generates a stable resting potential. This current was sensitive to tolbutamide, an ATP-sensitive potassium channel (KATP) antagonist. After its inhibition, quiet neurons start to fire spontaneously, while the behavior of active neurons was not affected. On the other hand, in active neurons, KATP agonist diazoxide activated a conductance similar to the KATP conductance of quiet neurons and stopped spontaneous firing. According to the effect of KATP channels on CW neuron firing, glycinergic neurotransmission in DCN was increased by tolbutamide and decreased by diazoxide. Finally, slices incubated with the tinnitus-inducing agent sodium salicylate presented more quiet neurons expressing the KATP conductance, which increased the proportion of quiet neurons. Our results reveal an unexpected role of KATP channels in controlling the spontaneous firing of neurons. Additionally, changes in KATP channel activity of cartwheel neurons can be related to the DCN hyperactivity seen in tinnitus.

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“…In fusiform cells, ECs are involved in acetylcholine-induced plasticity changes at parallel fiber synapses ( 94 ) which have been correlated with tinnitus ( 95 ). Prolonged exposure to high doses of salicylate (a well-known tinnitus inducer) increases EC release in the DCN, thus changing molecular layer plasticity ( 96 ). Unfortunately, cannabinoid modulation of this circuit has not yielded effective tinnitus treatments [see discussion in ( 97 )].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, several immune components and mechanisms known to be affected by EC modulation are also present in the auditory system, both peripheral and central. In the mammalian auditory system, EC system components or effects have been found in the cochlea ( 80 ), cochlear nuclei ( 93 , 96 , 233 ), MNTB ( 234 ), inferior colliculus ( 235 , 236 ), and auditory cortex ( 237 ).…”

Section: Introductionmentioning

confidence: 99%

Cannabinoids, Inner Ear, Hearing, and Tinnitus: A Neuroimmunological Perspective

et al. 2020

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Cannabis has been used for centuries for recreational and therapeutic purposes. Whereas, the recreative uses are based on the psychotropic effect of some of its compounds, its therapeutic effects range over a wide spectrum of actions, most of which target the brain or the immune system. Several studies have found cannabinoid receptors in the auditory system, both at peripheral and central levels, thus raising the interest in cannabinoid signaling in hearing, and especially in tinnitus, which is affected also by anxiety, memory, and attention circuits where cannabinoid effects are well described. Available studies on animal models of tinnitus suggest that cannabinoids are not likely to be helpful in tinnitus treatment and could even be harmful. However, the pharmacology of cannabinoids is very complex, and most studies focused on neural CB1R-based responses. Cannabinoid effects on the immune system (where CB2Rs predominate) are increasingly recognized as essential in understanding nervous system pathological responses, and data on immune cannabinoid targets have emerged in the auditory system as well. In addition, nonclassical cannabinoid targets (such as TRP channels) appear to play an important role in the auditory system as well. This review will focus on neuroimmunological mechanisms for cannabinoid effects and their possible use as protective and therapeutic agents in the ear and auditory system, especially in tinnitus.

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Enhancement of Endocannabinoid-dependent Depolarization-induced Suppression of Excitation in Glycinergic Neurons by Prolonged Exposure to High Doses of Salicylate

Cited by 12 publications

References 48 publications

Long‑term treatment with salicylate enables NMDA receptors and impairs AMPA receptors in C57BL/6J mice inner hair cell ribbon synapse

Long‑term treatment with salicylate enables NMDA receptors and impairs AMPA receptors in C57BL/6J mice inner hair cell ribbon synapse

ATP-sensitive K⁺channels control the spontaneous firing of a glycinergic interneuron in the auditory brainstem

Cannabinoids, Inner Ear, Hearing, and Tinnitus: A Neuroimmunological Perspective

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Enhancement of Endocannabinoid-dependent Depolarization-induced Suppression of Excitation in Glycinergic Neurons by Prolonged Exposure to High Doses of Salicylate

Cited by 12 publications

References 48 publications

Long‑term treatment with salicylate enables NMDA receptors and impairs AMPA receptors in C57BL/6J mice inner hair cell ribbon synapse

Long‑term treatment with salicylate enables NMDA receptors and impairs AMPA receptors in C57BL/6J mice inner hair cell ribbon synapse

ATP-sensitive K+channels control the spontaneous firing of a glycinergic interneuron in the auditory brainstem

Cannabinoids, Inner Ear, Hearing, and Tinnitus: A Neuroimmunological Perspective

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ATP-sensitive K⁺channels control the spontaneous firing of a glycinergic interneuron in the auditory brainstem