Cochlear Kainate Receptors

Peppi, Marcello; Landa, Melissa; Sewell, William F.

doi:10.1007/s10162-011-0309-9

Cited by 18 publications

(18 citation statements)

References 21 publications

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“…In contrast, Peppi et al (2012) showed that some puncta representing each of the 5 KAR subunits could colocalize with GluA2 puncta at the base of the IHCs of CBA/CaJ mice. We found that GluA2-immunoreactivity (using the same monoclonal antibody that was used in Peppi et al, 2012) produced some puncta that do not colocalize with the ribbon and PSD markers.…”

Section: Discussionmentioning

confidence: 72%

“…Based on the X-gal staining pattern in cochleae from GluK5 KO mice as well as what is known from the literature (Peppi et al, 2012), we hypothesized that GluK5 and other KAR subunits (Lerma and Marques, 2013) are expressed in the postsynaptic membrane of afferent terminals in IHCs and also in both pre- and postsynaptic membranes of afferent terminals in OHCs.…”

Section: Resultsmentioning

confidence: 97%

“…For GluA2 (clone 6C4; Chemicon, 1:200; a monoclonal, N-terminus antibody, well characterized and specific for GluA2, and used previously for cochlea studies; Eybalin et al, 2004; Peppi et al, 2012; Martinez-Monedero, et al, 2012) labeling, a different labeling method was required because labeling was unsuccessful using the method mentioned above; tissue was fixed in 4% paraformaldehyde for 1 hr at 4°C, permeabilized with 0.5% Nonidet P-40 for 10 min at 4°C, and incubated in the primary antibody in PBS for 3 hr at room temperature (Martinez-Monedero, et al, 2012). …”

Section: Methodsmentioning

confidence: 99%

“…Another study reported that KARs are expressed in IHC afferent synapses and suggested that KARs contribute to hair cell acoustic transmission, based on physiological data using a GluK1-specific antagonist (Peppi et al, 2012). These findings suggest that KARs are involved in normal cochlear function for synaptic transmission or modulation.…”

Section: Introductionmentioning

confidence: 99%

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Localization of kainate receptors in inner and outer hair cell synapses

et al. 2014

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Glutamate plays a role in hair cell afferent transmission, but the receptors that mediate neurotransmission between outer hair cells (OHCs) and type II ganglion neurons are not well defined. A previous study using in situ hybridization showed that several kainate-type glutamate receptor (KAR) subunits are expressed in cochlear ganglion neurons. To determine whether KARs are expressed in hair cell synapses, we performed X-gal staining on mice expressing lacZ driven by the GluK5 promoter, and immunolabeling of glutamate receptors in whole-mount mammalian cochleae. X-gal staining revealed GluK5 expression in both type I and type II ganglion neurons and OHCs in adults. OHCs showed X-gal reactivity throughout maturation from postnatal day 4 (P4) to 1.5 months. Immunoreactivity for GluK5 in IHC afferent synapses appeared to be postsynaptic, similar to GluA2 (GluR2; AMPA-type glutamate receptor (AMPAR) subunit), while GluK2 may be on both sides of the synapses. In OHC afferent synapses, immunoreactivity for GluK2 and GluK5 was found, although GluK2 was only in those synapses bearing ribbons. GluA2 was not detected in adult OHC afferent synapses. Interestingly, GluK1, GluK2 and GluK5 were also detected in OHC efferent synapses, forming several active zones in each synaptic area. At P8, GluA2 and all KAR subunits except GluK4 were detected in OHC afferent synapses in the apical turn, and GluA2, GluK1, GluK3 decreased dramatically in the basal turn. These results indicate that AMPARs and KARs (GluK2/GluK5) are localized to IHC afferent synapses, while only KARs (GluK2/GluK5) are localized to OHC afferent synapses in adults. Glutamate spillover near OHCs may act on KARs in OHC efferent terminals to modulate transmission of acoustic information and OHC electromotility.

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Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Localization of kainate receptors in inner and outer hair cell synapses

et al. 2014

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“…Measurements were made from the right ear of female Mongolian gerbils weighing between 45 and 70 g. Ouabain, which abolishes auditory nerve responses while maintaining hair cell responses (e.g., Schmiedt et al, 2002;Lang et al, 2005;Peppi et al, 2012;Yuan et al, 2014) was used to quantify the extent to which neural excitation contributes to f Tr . All experiments were acute in that on a given day a pharmaceutical treatment was applied, an experiment performed, and the animal was sacrificed.…”

Section: A Overviewmentioning

confidence: 99%

An analysis of cochlear response harmonics: Contribution of neural excitation

Chertoff

Kamerer

Peppi

et al. 2015

The Journal of the Acoustical Society of America

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In this report an analysis of cochlear response harmonics is developed to derive a mathematical function to estimate the gross mechanics involved in the in vivo transfer of acoustic sound into neural excitation (f Tr ). In a simulation it is shown that the harmonic distortion from a nonlinear system can be used to estimate the nonlinearity, supporting the next phase of the experiment: Applying the harmonic analysis to physiologic measurements to derive estimates of the unknown, in vivo f Tr . From gerbil ears, estimates of f Tr were derived from cochlear response measurements made with an electrode at the round window niche from 85 Hz tone bursts. Estimates of f Tr before and after inducing auditory neuropathy-loss of auditory nerve responses with preserved hair cell responses from neurotoxic treatment with ouabain-showed that the neural excitation from low-frequency tones contributes to the magnitude of f Tr but not the sigmoidal, saturating, nonlinear morphology.

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GluK2 Is a Target for Gene Therapy in Drug‐Resistant Temporal Lobe Epilepsy

Boileau

Deforges

Peret

et al. 2023

Annals of Neurology

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ObjectiveTemporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule cells (DGCs) crea an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5‐containing kainate receptors (KARs). TLE patients are often resistant to anti‐seizure medications and suffer significant comorbidities; hence, there is an urgent need for novel therapies. Previously, we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE.MethodsWe combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug‐resistant TLE.ResultsHere, we confirmed the translational potential of KAR suppression using a non‐selective KAR antagonist that markedly attenuated interictal‐like epileptiform discharges (IEDs) in TLE patient‐derived hippocampal slices. An adeno‐associated virus (AAV) serotype‐9 vector expressing anti‐grik2 miRNA was engineered to specifically downregulate GluK2 expression. Direct delivery of AAV9‐anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs.InterpretationOur gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof‐of‐concept for a gene therapy approach targeting GluK2 KARs for drug‐resistant TLE patients. ANN NEUROL 2023

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Cochlear Kainate Receptors

Cited by 18 publications

References 21 publications

Localization of kainate receptors in inner and outer hair cell synapses

Localization of kainate receptors in inner and outer hair cell synapses

An analysis of cochlear response harmonics: Contribution of neural excitation

GluK2 Is a Target for Gene Therapy in Drug‐Resistant Temporal Lobe Epilepsy

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