Cochlear ribbon synapse maturation requires Nlgn1 and Nlgn3

Ramírez, Miguel Ángel; Ninoyu, Yuzuru; Miller, Cayla M.; Andrade, Leonardo R.; Edassery, Seby L.; Bomba-Warczak, Ewa; Ortega, Briana; Manor, Uri; Rutherford, Mark A.; Friedman, Rick A.; Savas, Jeffrey N.

doi:10.1016/j.isci.2022.104803

Cited by 8 publications

(13 citation statements)

References 57 publications

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“…The mechanisms are still unclear, but evidence shows that AMPARs convey a retrograde trans-synaptic signal essential for presynaptic maturation ( Tracy et al, 2011 ). AMPAR subunits in the cochlea may interact with the trans-synaptic adhesion factors Neuroligins and Neurexins ( Heine et al, 2008 ; Hickox et al, 2017 ; Ramirez et al, 2022 ). GluA3 is required for the functional development of the presynaptic terminal and the structural maturation of SV size in endbulb auditory nerve synapses in the cochlear nucleus ( Antunes et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…PSD95 interacts with the cell adhesion proteins Neuroligins ( Irie et al, 1997 ; Jeong et al, 2019 ). Neuroligin-3 and to a lesser extent Neuroligin-1 are essential to cochlear function ( Ramirez et al, 2022 ). In the CNS, alignment of postsynaptic AMPARs, PSD95, and Neuroligin-1 together with the presynaptic protein RIM form nanocolumns ( Tang et al, 2016 ) thought to represent essential elements of trans-synaptic connections.…”

Section: Discussionmentioning

confidence: 99%

“…In the CNS, alignment of postsynaptic AMPARs, PSD95, and Neuroligin-1 together with the presynaptic protein RIM form nanocolumns ( Tang et al, 2016 ) thought to represent essential elements of trans-synaptic connections. The existence of such nanocolumns at ribbon synapses, where several release sites may reside around each ribbon, is unknown, but the same proteins are present ( Jung et al, 2015 ; Krinner et al, 2017 ; Picher et al, 2017 ; Hickox et al, 2017 ; Ramirez et al, 2022 ). To understand further the synaptic mechanisms of hearing and hearing loss, it will be essential to identify the full complement of cleft-spanning adhesion proteins that interact with AMPARs at IHC synapses, in particular with GluA3.…”

Section: Discussionmentioning

confidence: 99%

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GluA3 subunits are required for appropriate assembly of AMPAR GluA2 and GluA4 subunits on cochlear afferent synapses and for presynaptic ribbon modiolar–pillar morphology

Rutherford¹,

Bhattacharyya²,

Xiao³

et al. 2023

eLife

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Cochlear sound encoding depends on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), but reliance on specific pore-forming subunits is unknown. With 5-week-old male C57BL/6J Gria3 knockout mice (i.e., subunit GluA3KO) we determined cochlear function, synapse ultrastructure and AMPAR molecular anatomy at ribbon synapses between inner hair cells (IHCs) and spiral ganglion neurons. GluA3KO and wild-type (GluA3WT) mice reared in ambient sound pressure level (SPL) of 55-75 dB had similar auditory brainstem response (ABR) thresholds, wave-1 amplitudes and latencies. Postsynaptic densities (PSDs), presynaptic ribbons, and synaptic vesicle sizes were all larger on the modiolar side of the IHCs from GluA3WT, but not GluA3KO, demonstrating GluA3 is required for modiolar-pillar synapse differentiation. Presynaptic ribbons juxtaposed with postsynaptic GluA2/4 subunits were similar in quantity, however, lone ribbons were more frequent in GluA3KO and GluA2-lacking synapses were observed only in GluA3KO. GluA2 and GluA4 immunofluorescence volumes were smaller on the pillar side than the modiolar side in GluA3KO, despite increased pillar-side PSD size. Overall, the fluorescent puncta volumes of GluA2 and GluA4 were smaller in GluA3KO than GluA3WT. However, GluA3KO contained less GluA2 and greater GluA4 immunofluorescence intensity relative to GluA3WT (3-fold greater mean GluA4:GluA2 ratio). Thus, GluA3 is essential in development, as germline disruption of Gria3 caused anatomical synapse pathology before cochlear output became symptomatic by ABR. We propose the hearing loss in older male GluA3KO mice results from progressive synaptopathy evident in 5-week-old mice as decreased abundance of GluA2 subunits and an increase in GluA2-lacking, GluA4-monomeric Ca2+-permeable AMPARs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

GluA3 subunits are required for appropriate assembly of AMPAR GluA2 and GluA4 subunits on cochlear afferent synapses and for presynaptic ribbon modiolar–pillar morphology

Rutherford¹,

Bhattacharyya²,

Xiao³

et al. 2023

eLife

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“…Work in mouse auditory inner hair cells (IHCs) has implicated the CAM Neuroplastin (Np55/Np65) and the neuronal CAM (NrCAM) in the development of IHC ribbon synapses (Carrott et al, 2016; Harley et al, 2018; Newton et al, 2022). More recent work in mouse found that a well-studied family of postsynaptic CAMs, neuroligins (Nlgns), are important for ribbon-synapse assembly (Ramirez et al, 2022). This work found that mice lacking NLGN1/3 have fewer ribbon synapses in IHCs and impaired hearing.…”

Section: Introductionmentioning

confidence: 99%

Presynaptic Nrxn3 is essential for ribbon-synapse assembly in hair cells

Jukic,

Lei,

Cebul

et al. 2024

Preprint

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Hair cells of the inner ear rely on specialized ribbon synapses to transmit sensory information to the central nervous system. The molecules required to assemble these synapses are not fully understood. We show that Nrxn3, a presynaptic adhesion molecule, is critical for ribbon-synapse assembly in hair cells. In both mouse and zebrafish models, loss of Nrxn3 results in significantly fewer intact ribbon synapses. In zebrafish we demonstrate that a 60% loss of synapses in nrxn3 mutants dramatically reduces both presynaptic responses in hair cells and postsynaptic responses in afferent neurons. Despite a reduction in synapse function in this model, we find no deficits in the acoustic startle response, a behavior reliant on these synapses. Overall, this work demonstrates that Nrxn3 is a critical and conserved molecule required to assemble ribbon synapses. Understanding how ribbon synapses assemble is a key step towards generating novel therapies to treat forms of age-related and noise-induced hearing loss that occur due to loss of ribbon synapses.

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“…The tetraspan protein clarin‐1, interacting with harmonin, has also been proposed as a possible member of the IHC transsynaptic adhesion complex (Dulon et al , 2018). While there is some preliminary work on the function of synaptic adhesion proteins, such as neurexins (Sons et al , 2006) and neuroligins (Hoon et al , 2009; Ramirez et al , 2022), much remains to be done to elucidate the molecular players for implementing synaptic heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Diversity matters — extending sound intensity coding by inner hair cells via heterogeneous synapses

Moser,

Karagulyan,

Neef

et al. 2023

The EMBO Journal

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Our sense of hearing enables the processing of stimuli that differ in sound pressure by more than six orders of magnitude. How to process a wide range of stimulus intensities with temporal precision is an enigmatic phenomenon of the auditory system. Downstream of dynamic range compression by active cochlear micromechanics, the inner hair cells (IHCs) cover the full intensity range of sound input. Yet, the firing rate in each of their postsynaptic spiral ganglion neurons (SGNs) encodes only a fraction of it. As a population, spiral ganglion neurons with their respective individual coding fractions cover the entire audible range. How such “dynamic range fractionation” arises is a topic of current research and the focus of this review. Here, we discuss mechanisms for generating the diverse functional properties of SGNs and formulate testable hypotheses. We postulate that an interplay of synaptic heterogeneity, molecularly distinct subtypes of SGNs, and efferent modulation serves the neural decomposition of sound information and thus contributes to a population code for sound intensity.

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Cochlear ribbon synapse maturation requires Nlgn1 and Nlgn3

Cited by 8 publications

References 57 publications

GluA3 subunits are required for appropriate assembly of AMPAR GluA2 and GluA4 subunits on cochlear afferent synapses and for presynaptic ribbon modiolar–pillar morphology

GluA3 subunits are required for appropriate assembly of AMPAR GluA2 and GluA4 subunits on cochlear afferent synapses and for presynaptic ribbon modiolar–pillar morphology

Presynaptic Nrxn3 is essential for ribbon-synapse assembly in hair cells

Diversity matters — extending sound intensity coding by inner hair cells via heterogeneous synapses

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