High doses of salicylate reduces glycinergic inhibition in the dorsal cochlear nucleus of the rat

Zugaib, João; Ceballos, Cesar C.; Leão, Ricardo M.

doi:10.1016/j.heares.2015.10.008

Cited by 25 publications

(37 citation statements)

References 36 publications

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“…Coronal slices containing DCN were obtained as in Zugaib et al (2016). Briefly brains were removed and cut in cold solution whose composition in mM was: NaCl (87), NaHCO 3 (25), KCl (2.5), NaH 2 PO 4 (1.25), CaCl 2 (0.5), MgCl 2 (7), glucose (25), sucrose (75), 335 mOsm/kgH 2 O, pH 7.4 when bubbled with carbogenic mixture (95% O 2 and 5% CO 2 ).…”

Section: Methodsmentioning

confidence: 99%

“…Single cells were visualized with IR interference contrast optics and recorded using patch pipettes in either voltage- or current-clamp modes. Fusiform neurons were identified based on their electrophysiological and morphological characteristics (for more details see Tzounopoulos et al, 2004; Zugaib et al, 2016). Pipettes were filled with a K + -based internal solution containing (in mM): 113 K -gluconate, 4.5 MgCl 2 , 14 tris-phosphocreatine, 9 HEPES, 0.1 EGTA, 4 Na-ATP, 0.3 tris-GTP, 10 sucrose, pH 7.3, ∼300 mOsmol.…”

Section: Methodsmentioning

confidence: 99%

“…Fusiform neurons are divided in two populations based on their firing properties: one presenting spontaneous firing at rest, termed active, and another one which does not produce spontaneous firing, named quiet (Leao et al, 2012; Zugaib et al, 2016). These two firing states are produced by differential expression of an intrinsic ionic conductance (Leao et al, 2012) namely, the differential expression of an inwardly rectifying potassium current ( I Kir ), which sets the resting membrane potential (RMP) at different voltage determining whether fusiform neurons fire spontaneously or not.…”

Section: Introductionmentioning

confidence: 99%

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Ih Equalizes Membrane Input Resistance in a Heterogeneous Population of Fusiform Neurons in the Dorsal Cochlear Nucleus

Ceballos

Roque

et al. 2016

Front. Cell. Neurosci.

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In a neuronal population, several combinations of its ionic conductances are used to attain a specific firing phenotype. Some neurons present heterogeneity in their firing, generally produced by expression of a specific conductance, but how additional conductances vary along in order to homeostatically regulate membrane excitability is less known. Dorsal cochlear nucleus principal neurons, fusiform neurons, display heterogeneous spontaneous action potential activity and thus represent an appropriate model to study the role of different conductances in establishing firing heterogeneity. Particularly, fusiform neurons are divided into quiet, with no spontaneous firing, or active neurons, presenting spontaneous, regular firing. These modes are determined by the expression levels of an intrinsic membrane conductance, an inwardly rectifying potassium current (IKir). In this work, we tested whether other subthreshold conductances vary homeostatically to maintain membrane excitability constant across the two subtypes. We found that Ih expression covaries specifically with IKir in order to maintain membrane resistance constant. The impact of Ih on membrane resistance is dependent on the level of IKir expression, being much smaller in quiet neurons with bigger IKir, but Ih variations are not relevant for creating the quiet and active phenotypes. Finally, we demonstrate that the individual proportion of each conductance, and not their absolute conductance, is relevant for determining the neuronal firing mode. We conclude that in fusiform neurons the variations of their different subthreshold conductances are limited to specific conductances in order to create firing heterogeneity and maintain membrane homeostasis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ih Equalizes Membrane Input Resistance in a Heterogeneous Population of Fusiform Neurons in the Dorsal Cochlear Nucleus

Ceballos

Roque

et al. 2016

Front. Cell. Neurosci.

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“…A potentiated depression of the excitatory glutamatergic input to the CW neuron during trains on intense activity of the PF could reduce the feed‐forward inhibition on the fusiform neuron, resulting in an increased firing of these neurons, which could be potentially important for the tinnitus induced by salicylate. Previous observations showed that salicylate decreases the spontaneous firing of CW neurons in the slice and spontaneous glycinergic transmission on fusiform neurons (Zugaib et al, ), showing that salicylate can decrease inhibition in the DCN. Because administration of CB agonists to rats produces psychophysical symptoms of tinnitus similar to salicylate administration (Zheng et al, ) we originally postulated that activation of EC system in the DCN could be a mechanism used by salicylate to induce tinnitus.…”

Section: Discussionmentioning

confidence: 90%

“…CW neurons were identified by their location in the slice and their action potential pattern as described (Zugaib et al, ). Glutamatergic excitatory postsynaptic currents (EPSCs) were evoked using a bipolar Ag/AgCl wire electrode inside a theta‐glass micropipette, filled with aCSF, placed in the PF layer, and recorded at a holding potential of −80 mV.…”

Section: Methodsmentioning

confidence: 99%

Inhibitors of oxidative and hydrolytic endocannabinoid degradation do not enhance depolarization‐induced suppression of excitation on dorsal cochlear nucleus glycinergic neurons

Zugaib

Leão

2017

Synapse

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Neurons from the dorsal cochlear nucleus (DCN) present endocannabinoid (EC) dependent short-term synaptic plasticity in the form of depolarization-induced suppression of excitation (DSE). Postsynaptic calcium influx promotes EC synthesis and depression of neurotransmission. ECs can be degraded by a hydrolytic and an oxidative pathway, the latter via the enzyme cyclooxygenase 2 (COX-2). Hyperactivity in the DCN is related to the development of tinnitus, which can be induced by high doses of salicylate, a COX-2 inhibitor. Since EC-dependent plasticity in the DCN can affect its excitation-inhibition balance, we investigated the impact of inhibitors of both oxidative and hydrolytic EC metabolism on the DSE from the synapses between the parallel fibers and cartwheel neurons (PF-CW) in the DCN. We found that inhibitors of COX-2 (ibuprofen and indomethacin) did not alter DSE at the PF-CW synapse. Salicylate also did not alter DSE. However, we found that inhibitors of the hydrolytic pathway did not affect DSE magnitude, but surprisingly speeded DSE decay. We conclude that oxidative EC degradation in the PF-CW synapse is not relevant for termination of DSE and are probably not important for controlling this form of synaptic plasticity in the DCN PF-CW synapse. The lack of effect on DSE of high doses of salicylate also suggests that it is not acting by increasing DSE in the PF-CWC synapse. However, the counter intuitive effect of the hydrolytic inhibitors shows that increasing EC on this synapse have more complex effects on DSE.

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Functional Connectivity Alterations and Molecular Characterization of the Anterior Cingulate Cortex in Tinnitus Pathology without Hearing Loss

Fan,

Guan,

Zhong

et al. 2023

Advanced Science

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Compared with individuals with hearing loss, tinnitus patients without hearing loss have more psychological or emotional problems. Tinnitus is closely associated to abnormal metabolism and function of the limbic system, a key brain region for emotion experience, but the underlying molecular mechanism remains unknown. Using whole‐brain microvasculature dynamics imaging, the anterior cingulate cortex (ACC) is identified as a key brain region of limbic system involve in the onset of salicylate‐induced tinnitus in mice. In the tinnitus group, there is enhanced purine metabolism, oxidative phosphorylation, and a distinct pattern of phosphorylation in glutamatergic synaptic pathway according to the metabolome profiles, quantitative proteomic, and phosphoproteomic data of mice ACC tissue. Electroencephalogram in tinnitus patients with normal hearing thresholds show that the functional connectivity between pregenual anterior cingulate cortex and the primary auditory cortex is significantly increased for high‐gamma frequency band, which is positively correlated with the serum glutamate level. These findings indicate that ACC plays an important role in the pathophysiology of tinnitus by interacting with the primary auditory cortex and provide potential molecular targets in the ACC for tinnitus treatment.

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High doses of salicylate reduces glycinergic inhibition in the dorsal cochlear nucleus of the rat

Cited by 25 publications

References 36 publications

Ih Equalizes Membrane Input Resistance in a Heterogeneous Population of Fusiform Neurons in the Dorsal Cochlear Nucleus

Ih Equalizes Membrane Input Resistance in a Heterogeneous Population of Fusiform Neurons in the Dorsal Cochlear Nucleus

Inhibitors of oxidative and hydrolytic endocannabinoid degradation do not enhance depolarization‐induced suppression of excitation on dorsal cochlear nucleus glycinergic neurons

Functional Connectivity Alterations and Molecular Characterization of the Anterior Cingulate Cortex in Tinnitus Pathology without Hearing Loss

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