Ca<sup>2+</sup>-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse

Sebe, Joy Y.; Cho, Soyoun; Sheets, Lavinia; Rutherford, Mark A.; Gersdorff, Henrique von; Raible, David W.

doi:10.1523/jneurosci.3644-16.2017

Cited by 67 publications

(110 citation statements)

References 65 publications

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“…Briefly, after cardiac perfusion with 4% PFA, for whole-mount preparations, organ of Corti and spiral ganglion were isolated from the cochlea in three pieces containing the apical, middle, and basal thirds. Antibodies: CtBP2 mouse (BD Biosciences; RRID:AB_399431), Ca V 1.3 rabbit (Alomone Labs; RRID:AB_2039775), GluA3 goat (Santa Cruz Biotechnology; RRID: AB_2113895), and Myosin7a rabbit (Proteus Biosciences; RRID: AB_2314838) primary antibodies were used with species-appropriate secondary antibodies conjugated to AlexaFluor (Invitrogen) fluorophores excited by 488, 555, or 647 nm light in triple-labeled samples as previously described (Jing et al, 2013;Sebe et al, 2017). Samples were batch processed using the same reagent solutions in six cohorts, each including exposed and unexposed Vglut3 WT , Vglut3 ϩ/Ϫ , and Vglut3 KO mice.…”

Section: Methodsmentioning

confidence: 99%

“…macological experiments and in response to sound overexposure, ANF postsynaptic terminals swell and burst, producing postsynaptic damage and vacuolization (Puel et al, 1994;Wang and Green, 2011). The excitotoxic mechanisms of glutamate in the organ of Corti are unknown and may involve Ca 2ϩ -permeable AMPA receptors (Puel et al, 1998;Eybalin et al, 2004;Sebe et al, 2017). The question of whether excess synaptic glutamate release drives noise-induced synapse loss has not been directly tested with a genetic approach.…”

Section: Significance Statementmentioning

confidence: 99%

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Vesicular Glutamatergic Transmission in Noise-Induced Loss and Repair of Cochlear Ribbon Synapses

Kim¹,

Payne²,

Yang-Hood³

et al. 2019

J. Neurosci.

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117

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Noise-induced excitotoxicity is thought to depend on glutamate. However, the excitotoxic mechanisms are unknown, and the necessity of glutamate for synapse loss or regeneration is unclear. Despite absence of glutamatergic transmission from cochlear inner hair cells in mice lacking the vesicular glutamate transporter-3 (Vglut3 KO), at 9-11 weeks, approximately half the number of synapses found in Vglut3 WT were maintained as postsynaptic AMPA receptors juxtaposed with presynaptic ribbons and voltage-gated calcium channels (Ca V 1.3). Synapses were larger in Vglut3 KO than Vglut3 WT. In Vglut3 WT and Vglut3 ϩ/Ϫ mice, 8-16 kHz octave-band noise exposure at 100 dB sound pressure level caused a threshold shift (ϳ40 dB) and a loss of synapses (Ͼ50%) at 24 h after exposure. Hearing threshold and synapse number partially recovered by 2 weeks after exposure as ribbons became larger, whereas recovery was significantly better in Vglut3 WT. Noise exposure at 94 dB sound pressure level caused auditory threshold shifts that fully recovered in 2 weeks, whereas suprathreshold hearing recovered faster in Vglut3 WT than Vglut3 ϩ/Ϫ. These results, from mice of both sexes, suggest that spontaneous repair of synapses after noise depends on the level of Vglut3 protein or the level of glutamate release during the recovery period. Noise-induced loss of presynaptic ribbons or postsynaptic AMPA receptors was not observed in Vglut3 KO , demonstrating its dependence on vesicular glutamate release. In Vglut3 WT and Vglut3 ϩ/Ϫ , noise exposure caused unpairing of presynaptic ribbons and presynaptic Ca V 1.3, but not in Vglut3 KO where Ca V 1.3 remained clustered with ribbons at presynaptic active zones. These results suggest that, without glutamate release, noise-induced presynaptic Ca 2ϩ influx was insufficient to disassemble the active zone. However, synapse volume increased by 2 weeks after exposure in Vglut3 KO , suggesting glutamate-independent mechanisms.

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Section: Methodsmentioning

confidence: 99%

Section: Significance Statementmentioning

confidence: 99%

Vesicular Glutamatergic Transmission in Noise-Induced Loss and Repair of Cochlear Ribbon Synapses

Kim¹,

Payne²,

Yang-Hood³

et al. 2019

J. Neurosci.

Self Cite

117

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“…EPSCs were evoked at a frequency of 1 Hz and an activity-dependent block of the EPSC was observed in the presence of IEM-1460, a selective open-channel antagonist of GluA2-lacking AMPARs ( Fig. 1 A, B; Sebe et al, 2017;Twomey et al, 2018). IEM-1460 blocked 78.1 Ϯ 5.1% of the EPSC amplitude in immature P4 -P5 animals, whereas a progressively smaller effect of the drug on the EPSC amplitude was observed as the age of the animals increased (P8 -P11: 68.0 Ϯ 2.6%, P18 -P22: 40.8 Ϯ 2.7%, P30 -P34: 33.3 Ϯ 5.0%; Fig.…”

Section: Isolating Ca 2؉ Permeable Epscs With Iem-1460mentioning

confidence: 99%

“…Diversity of AMPARs and release probability at auditory brainstem nuclei CP-AMPARs are found in a subclass interneurons in the neocortex, where they regulate the dynamic balance of excitation and inhibition (Hull et al, 2009;Lalanne et al, 2016). At the inner hair cell synapse of the cochlea, a ribbon-type synapse, CP-AMPARs are expressed at the afferent fibers before the onset of hearing and their expression declines with maturation (Eybalin et al, 2004;Reijntjes and Pyott, 2016), although some receptors may remain in mature fibers (Sebe et al, 2017). Likewise, in the superior paraolivary nucleus of mice, a mixed population of CP-AMPARs and Ca 2ϩ -impermeable AMPARs were present before hearing onset; however, upon maturation, the population was composed primarily of Ca 2ϩ -impermeable AMPARs (Felix and Magnusson, 2016).…”

Section: Synaptic Ampar Subunits Change During Developmentmentioning

confidence: 99%

“…In several brain regions, CP-AMPARs serve important functions in the induction and modulation of activity-dependent synaptic plasticity at developing and mature synapses (Jia et al, 1996;Plant et al, 2006;Kim and von Gersdorff, 2016;Park et al, 2016). Additionally, Ca 2ϩ permeability through this receptor regulates neuronal Ca 2ϩ -induced excitotoxicity (Carriedo et al, 1998;Noh et al, 2005;Sebe et al, 2017) and the progression of several CNS pathologies are dependent on Ca 2ϩ influx through these receptors (Weiss, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Presynaptic Diversity Revealed by Ca²⁺-Permeable AMPA Receptors at the Calyx of Held Synapse

2019

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GluA2-lacking Ca 2ϩ -permeable AMPARs (CP-AMPARs) play integral roles in synaptic plasticity and can mediate excitotoxic cellular signaling at glutamatergic synapses. However, the developmental profile of functional CP-AMPARs at the auditory brainstem remains poorly understood. Through a combination of electrophysiological and live-cell Ca 2ϩ imaging from mice of either sex, we show that the synaptic release of glutamate from the calyx of Held nerve terminal activates CP-AMPARs in the principal cells of the medial nucleus of the trapezoid body in the brainstem. This leads to significant Ca 2ϩ influx through these receptors before the onset of hearing at postnatal day 12 (P12). Using a selective open channel blocker of CP-AMPARs, IEM-1460, we estimate that ϳ80% of the AMPAR population are permeable to Ca 2ϩ at immature P4 -P5 synapses. However, after the onset of hearing, Ca 2ϩ influx through these receptors was greatly reduced. We estimate that CP-AMPARs comprise approximately 40% and 33% of the AMPAR population at P18 -P22 and P30 -P34, respectively. By quantifying the rate of EPSC block by IEM-1460, we found an increased heterogeneity in glutamate release probability for adult-like calyces (P30 -P34). Using tetraethylammonium (TEA), a presynaptic potassium channel blocker, we show that the apparent reduction of CP-AMPARs in more mature synapses is not a consequence of presynaptic action potential (AP) speeding. Finally, through postsynaptic AP recordings, we show that inhibition of CP-AMPARs reduces spike fidelity in juvenile synapses, but not in more mature synapses. We conclude that the expression of functional CP-AMPARs declines over early postnatal development in the calyx of Held synapse.The calyx of Held synapse is pivotal to the circuitry that computes sound localization. Postsynaptic Ca 2ϩ influx via AMPARs may be critical for signaling the maturation of this brainstem synapse. The GluA4 subunit may dominate the AMPAR complex at mature synapses because of its fast gating kinetics and large unitary conductance. The expectation is that AMPARs dominated by GluA4 subunits should be highly Ca 2ϩ permeable. However, we find that Ca 2ϩ -permeable AMPAR expression declines during postnatal development. Using the rate of EPSC block by IEM-1460, an open channel blocker of Ca 2ϩ -permeable AMPARs, we propose a novel method to determine glutamate release probability and uncover an increased heterogeneity in release probability for more mature calyces of Held nerve terminals.

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Noise‐induced hippocampal oxidative imbalance and aminoacidergic neurotransmitters alterations in developing male rats: Influence of enriched environment during adolescence

Molina

Buján

Guelman

2021

Developmental Neurobiology

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Living in big cities might involuntarily expose people to high levels of noise causing auditory and/or extra‐auditory impairments, including adverse effects on central nervous system (CNS) areas such as the hippocampus. In particular, CNS development is a very complex process that can be altered by environmental stimuli. We have previously shown that noise exposure of developing rats can induce hippocampal‐related behavioral alterations. However, noise‐induced biochemical alterations had not been studied yet. Thus, the aim of this work was to assess whether early noise exposure can affect rat hippocampal oxidative state and aminoacidergic neurotransmission tone. Additionally, the effectiveness of an enriched environment (EE) as a neuroprotective strategy was evaluated. Male Wistar rats were exposed to different noise schemes at 7 or 15 days after birth. Upon weaning, some animals were transferred to an EE whereas others were kept in standard cages. Short‐ and long‐term measurements were performed to evaluate reactive oxygen species, thioredoxins levels and catalase activity as indicators of hippocampal oxidative status as well as glutamic acid decarboxylase and a subtype of glutamate transporter to evaluate aminoacidergic neurotransmission tone. Results showed noise‐induced changes in hippocampal oxidative state and aminoacidergic neurotransmission markers that lasted until adolescence and differed according to the scheme and the age of exposure. Finally, EE housing was effective in preventing some of these changes. These findings suggest that CNS development seems to be sensitive to the effects of stressors such as noise, as well as those of an environmental stimulation, favoring prompt and lasting molecular changes.

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Ca²⁺-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse

Cited by 67 publications

References 65 publications

Vesicular Glutamatergic Transmission in Noise-Induced Loss and Repair of Cochlear Ribbon Synapses

Vesicular Glutamatergic Transmission in Noise-Induced Loss and Repair of Cochlear Ribbon Synapses

Presynaptic Diversity Revealed by Ca²⁺-Permeable AMPA Receptors at the Calyx of Held Synapse

Noise‐induced hippocampal oxidative imbalance and aminoacidergic neurotransmitters alterations in developing male rats: Influence of enriched environment during adolescence

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Ca2+-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse

Cited by 67 publications

References 65 publications

Vesicular Glutamatergic Transmission in Noise-Induced Loss and Repair of Cochlear Ribbon Synapses

Vesicular Glutamatergic Transmission in Noise-Induced Loss and Repair of Cochlear Ribbon Synapses

Presynaptic Diversity Revealed by Ca2+-Permeable AMPA Receptors at the Calyx of Held Synapse

Noise‐induced hippocampal oxidative imbalance and aminoacidergic neurotransmitters alterations in developing male rats: Influence of enriched environment during adolescence

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Ca²⁺-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse

Presynaptic Diversity Revealed by Ca²⁺-Permeable AMPA Receptors at the Calyx of Held Synapse