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Open Access 01-06-2021 | Original Article

Neuroplastin expression is essential for hearing and hair cell PMCA expression

Authors: Xiao Lin, Michael G. K. Brunk, Pingan Yuanxiang, Andrew W. Curran, Enqi Zhang, Franziska Stöber, Jürgen Goldschmidt, Eckart D. Gundelfinger, Maike Vollmer, Max F. K. Happel, Rodrigo Herrera-Molina, Dirk Montag

Published in: Brain Structure and Function | Issue 5/2021

Abstract

Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice (Nptn^−/−) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn^−/− mice. Adult Nptn^−/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn^−/− mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn^−/− mice. Conditional ablation of neuroplastin in Nptn^{lox/loxEmx1Cre} mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult Nptn^{Δlox/loxPrCreERT} mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca²⁺ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.

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Amuti S, Tang Y, Wu S, Liu L, Huang L, Zhang H, Li H, Jiang F, Wang G, Liu X, Yuan Q (2016) Neuroplastin 65 mediates cognitive functions via excitatory/inhibitory synapse imbalance and ERK signal pathway. Neurobiol Learn Mem 127:72–83. https://doi.org/10.1016/j.nlm.2015.11.020CrossRefPubMed

Beesley P, Kraus M, Parolaro N (2014a) The neuroplastins: multifunctional neuronal adhesion molecules-involvement in behaviour and disease. Adv Neurobiol 8:61–89CrossRef

Beesley PW, Herrera-Molina R, Smalla KH, Seidenbecher C (2014b) The neuroplastin adhesion molecules: key regulators of neuronal plasticity and synaptic function. J Neurochem 131(3):268–283. https://doi.org/10.1111/jnc.12816CrossRefPubMed

Bhattacharya S, Herrera-Molina R, Sabanov V, Ahmed T, Iscru E, Stöber F, Richter K, Fischer KD, Angenstein F, Goldschmidt J, Beesley PW, Balschun D, Smalla KH, Gundelfinger ED, Montag D (2017) Genetically-induced retrograde amnesia of associative memories after neuroplastin ablation. Biol Psychiatry 81(2):124–135. https://doi.org/10.1016/j.biopsych.2016.03.2107CrossRefPubMed

Brunk MGK, Deane KE, Kisse M, Deliano M, Vieweg S, Ohl FW, Lippert MT, Happel MFK (2019) Optogenetic stimulation of the VtA modulates a frequency-specific gain of thalamocortical inputs in infragranular layers of the auditory cortex. Sci Rep 9(1):20385. https://doi.org/10.1038/s41598-019-56926-6CrossRefPubMedPubMedCentral

Burkard R (2006) Calibration of acoustic transients. Brain Res 1091(1):27–31. https://doi.org/10.1016/j.brainres.2006.02.132CrossRefPubMed

Carrott L, Bowl MR, Aguilar C, Johnson SL, Chessum L, West M, Morse S, Dorning J, Smart E, Hardisty-Hughes R, Ball G, Parker A, Barnard AR, MacLaren RE, Wells S, Marcotti W, Brown SDM (2016) Absence of neuroplastin-65 affects synaptogenesis in mouse inner hair cells and causes profound hearing loss. J Neurosci 36:222–234. https://doi.org/10.1523/JNEUROSCI.1808-15.2016CrossRefPubMedPubMedCentral

Chabot N, Butler BE, Lomber SG (2015) Differential modification of cortical and thalamic projections to cat primary auditory cortex following early- and late-onset deafness. J Comp Neurol 523:2297–2320. https://doi.org/10.1002/cne.23790CrossRefPubMed

Choy MK, Javierre BM, Williams SG, Baross SL, Liu Y, Wingett SW, Akbarov A, Wallace C, Freire-Pritchett P, Rugg-Gunn PJ, Spivakov M, Fraser P, Keavney BD (2018) Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks. Nat Commun 9(1):2526. https://doi.org/10.1038/s41467-018-04931-0. Erratum in: Nat Commun (2018) 9(1):4792.

Cruikshank SJ, Rose HJ, Metherate R (2002) Auditory thalamocortical synaptic transmission in vitro. J Neurophysiol 87:361–384CrossRef

Deane KE, Brunk MGK, Curran AW, Zempeltzi MM, Ma J, Lin X, Abela F, Aksit S, Deliano M, Ohl FW, Happel MFK (2020) Ketamine anesthesia induces gain enhancement via recurrent excitation in granular input layers of the auditory cortex. J Physiol. https://doi.org/10.1113/JP279705CrossRefPubMedPubMedCentral

Deliano M, Brunk MGK, El-Tabbal M, Zempeltzi MM, Happel MFK, Ohl FW (2018) Dopaminergic neuromodulation of high gamma stimulus phase-locking in gerbil primary auditory cortex mediated by D1/D5-receptors. Eur J Neurosci 51(5):1315–1327. https://doi.org/10.1111/ejn.13898CrossRefPubMed

Desrivières S, Lourdusamy A, Tao C, Toro R, Jia T, Loth E, Medina LM, Kepa A, Fernandes A, Ruggeri B, Carvalho FM, Cocks G, Banaschewski T, Barker GJ, Bokde AL, Büchel C, Conrod PJ, Flor H, Heinz A, Gallinat J, Garavan H, Gowland P, Brühl R, Lawrence C, Mann K, Martinot ML, Nees F, Lathrop M, Poline JB, Rietschel M, Thompson P, Fauth-Bühler M, Smolka MN, Pausova Z, Paus T, Feng J, Schumann G, IMAGEN Consortium (2014) Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents. Mol Psychiatry 20:263–274. https://doi.org/10.1038/mp.2013.197CrossRefPubMedPubMedCentral

Empson RM, Buckby LE, Kraus M, Bates KJ, Crompton MR, Gundelfinger ED, Beesley PW (2006) The cell adhesion molecule neuroplastin-65 inhibits hippocampal long-term potentiation via a mitogen-activated protein kinase p38-dependent reduction in surface expression of GluR1-containing glutamate receptors. J Neurochem 99:850–860. https://doi.org/10.1111/j.1471-4159.2006.04123.xCrossRefPubMed

Endepols H, Sommer S, Backes H, Wiedermann D, Graf R, Hauber W (2010) Effort-based decision making in the rat: an [18F]fluorodeoxyglucose micro positron emission tomography study. J Neurosci 30:9708–9714. https://doi.org/10.1523/JNEUROSCI.1202-10.2010CrossRefPubMedPubMedCentral

Fettiplace R, Nam JH (2019) Tonotopy in calcium homeostasis and vulnerability of cochlear hair cells. Hear Res 376:11–21. https://doi.org/10.1016/j.heares.2018.11.002CrossRefPubMed

Givre SJJ, Schroeder CEE, Arezzo JCC (1994) Contribution of extrastriate area V4 to the surface-recorded flash VEP in the awake macaque. Vis Res 34:415–428CrossRef

Gong D, Chi X, Ren K, Huang G, Zhou G, Yan N, Lei J, Zhou Q (2018) Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin. Nat Commun 9:3623. https://doi.org/10.1038/s41467-018-06075-7CrossRefPubMedPubMedCentral

Grati M, Aggarwal N, Strehler EE, Wenthold RJ (2006) Molecular determinants for differential membrane trafficking of PMCA1 and PMCA2 in mammalian hair cells. J Cell Sci 119:2995–3007. https://doi.org/10.1242/jcs.03030CrossRefPubMed

Happel MF, Jeschke M, Ohl FW (2010) Spectral integration in primary auditory cortex attributable to temporally precise convergence of thalamocortical and intracortical input. J Neurosci 30:11114–11127. https://doi.org/10.1523/JNEUROSCI.0689-10.2010CrossRefPubMedPubMedCentral

Henschke JU, Oelschlegel AM, Angenstein F, Ohl FW, Goldschmidt J, Kanold PO, Budinger E (2018) Early sensory experience influences the development of multisensory thalamocortical and intracortical connections of primary sensory cortices. Brain Struct Funct 223:1165–1190. https://doi.org/10.1007/s00429-017-1549-1CrossRefPubMed

Herrera-Molina R, Sarto-Jackson I, Montenegro-Venegas C, Heine M, Smalla KH, Seidenbecher CI, Beesley PW, Gundelfinger ED, Montag D (2014) Structure of excitatory synapses and GABAA receptor localization at inhibitory synapses are regulated by neuroplastin-65. J Biol Chem 289:8973–8988. https://doi.org/10.1074/jbc.M113.514992CrossRefPubMedPubMedCentral

Herrera-Molina R, Mlinac-Jerkovic K, Ilic K, Stöber F, Vemula SK, Sandoval M, Milosevic NJ, Simic G, Smalla KH, Goldschmidt J, Bognar SK, Montag D (2017) Neuroplastin deletion in glutamatergic neurons impairs brain functions and calcium regulation: implication for cognitive deterioration. Sci Rep 7:7273. https://doi.org/10.1038/s41598-017-07839-9CrossRefPubMedPubMedCentral

Kolodziej A, Lippert M, Angenstein F, Neubert J, Pethe A, Grosser OS, Amthauer H, Schroeder UH, Reymann KG, Scheich H, Ohl FW, Goldschmidt J (2014) SPECT-imaging of activity-dependent changes in regional cerebral blood flow induced by electrical and optogenetic self-stimulation in mice. Neuroimage 103:171–180. https://doi.org/10.1016/j.neuroimage.2014.09.023CrossRefPubMed

Korthals M, Langnaese K, Smalla KH, Kähne T, Herrera-Molina R, Handschuh J, Lehmann AC, Mamula D, Naumann M, Seidenbecher C, Zuschratter W, Tedford K, Gundelfinger ED, Montag D, Fischer KD, Thomas U (2017) A complex of neuroplastin and plasma membrane calcium ATPase controls T cell activation. Sci Rep 7:8358. https://doi.org/10.1038/s41598-017-08519-4CrossRefPubMedPubMedCentral

Kozel PJ, Friedman RA, Erway LC, Yamoah EN, Liu LH, Riddle T, Duffy JJ, Doetschman T, EL MillerML C, Shull GE (1998) Balance and hearing deficits in mice with a null mutation in the gene encoding plasma membrane Ca2+-ATPase isoform 2. J Biol Chem 273:18693–18696CrossRef

Langnaese K, Beesley PW, Gundelfinger ED (1997) Synaptic membrane glycoproteins gp65 and gp55 are new members of the immunoglobulin superfamily. J Biol Chem 272:821–827CrossRef

Li H, Liu Y, Gao X, Liu L, Amuti S, Wu D, Jiang F, Huang L, Wang G, Zeng J, Ma B, Yuan Q (2019) Neuroplastin 65 modulates anxiety- and depression-like behavior likely through adult hippocampal neurogenesis and central 5-HT activity. FEBS J 286:3401–3415. https://doi.org/10.1111/febs.14865CrossRefPubMed

Ma Y, Hof PR, Grant SC, Blackband SJ, Bennett R, Slatest L, McGuigan MD, Benveniste H (2005) A three-dimensional digital atlas database of the adult C57BL/ 6 J mouse brain by magnetic resonance microscopy. Neuroscience 135:1203–1215CrossRef

Ma Y, Smith D, Hof PR, Foerster B, Hamilton S, Blackband SJ, Yu M (2008) Benveniste H (2008) In vivo 3D digital atlas database of the adult C57BL/6 J mouse brain by magnetic resonance microscopy. Front Neuroanat 2:1. https://doi.org/10.3389/neuro.05.001.2008CrossRefPubMedPubMedCentral

Mitzdorf U (1985) Current source-density method and application in cat cerebral cortex: investigation of evoked potentials and EEG phenomena. Physiol Rev 65:37–100. https://doi.org/10.1152/physrev.1985.65.1.37CrossRefPubMed

Owczarek S, Kiryushko D, Larsen MH, Kastrup JS, Gajhede M, Sandi C, Berezin V, Bock E, Soroka V (2010) Neuroplastin-55 binds to and signals through the fibroblast growth factor receptor. FASEB J 24:1139–1150. https://doi.org/10.1096/fj.09-140509CrossRefPubMed

Owczarek S, Soroka V, Kiryushko D, Larsen MH, Yuan Q, Sandi C, Berezin V, Bock E (2011) Neuroplastin-65 and a mimetic peptide derived from its homophilic binding site modulate neuritogenesis and neuronal plasticity. J Neurochem 117:984–994. https://doi.org/10.1111/j.1471-4159.2011.07269.xCrossRefPubMed

Perny M, Roccio M, Grandgirard D, Solyga M, Senn P, Leib SL (2016) The severity of infection determines the localization of damage and extent of sensorineural hearing loss in experimental pneumococcal meningitis. J Neurosci 36:7740–7749. https://doi.org/10.1523/JNEUROSCI.0554-16.2016CrossRefPubMedPubMedCentral

Reijntjes DOJ, Pyott SJ (2016) The afferent signaling complex: regulation of type I spiral ganglion neuron responses in the auditory periphery. Hear Res 336:1–16CrossRef

Ryugo DK (1992) The auditory nerve: peripheral innervation, cell body morphology, and central projections. In: Popper AN, Fay RR (eds) The mammalian auditory pathway: neuroanatomy. Springer, New York, pp 34–93

Saito A, Fujikura-Ouchi Y, Kuramasu A, Shimoda K, Akiyama K, Matsuoka H, Ito C (2007) Association study of putative promoter polymorphisms in the neuroplastin gene and schizophrenia. Neurosci Lett 411:168–173CrossRef

Sakaguchi M, Yamamoto M, Miyai M, Maeda T, Hiruma J, Murata H, Kinoshita R, Winarsa Ruma IM, Putranto EW, Inoue Y, Morizane S, Huh NH, Tsuboi R, Hibino T (2016) Identification of an S100A8 receptor neuroplastin-β and its heterodimer formation with EMMPRIN. J Invest Dermatol 136:2240–2250. https://doi.org/10.1016/j.jid.2016.06.617CrossRefPubMed

Saldeitis K, Happel MFK, Ohl FW, Scheich H, Budinger E (2014) Anatomy of the auditory thalamocortical system in the mongolian gerbil: nuclear origins and cortical field-, layer-, and frequency-specificities. J Comp Neurol 522:2397–2430. https://doi.org/10.1002/cne.23540CrossRefPubMed

Sarto-Jackson I, Milenkovic I, Smalla KH, Gundelfinger ED, Kaehne T, Herrera-Molina R, Thomas S, Kiebler MA, Sieghart W (2012) The cell adhesion molecule neuroplastin-65 is a novel interaction partner of gamma- aminobutyric acid type A receptors. J Biol Chem 287:14201–14214. https://doi.org/10.1074/jbc.M111.293175CrossRefPubMedPubMedCentral

Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke M, Kehlen A, Holzer M, Hutter-Paier B, Prokesch M, Windisch M, Jagla W, Schlenzig D, Lindner C, Rudolph T, Reuter G, Cynis H, Montag D, Demuth HU, Rossner S (2008) Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease-like pathology in vivo. Nat Med 14:1106–1111. https://doi.org/10.1038/nm.1872CrossRefPubMed

Schmidt N, Kollewe A, Constantin CE, Henrich S, Ritzau-Jost A, Bildl W, Saalbach A, Hallermann S, Kulik A, Fakler B, Schulte U (2017) Neuroplastin and basigin are essential auxiliary subunits of plasma membrane Ca²⁺-ATPases and key regulators of Ca²⁺ clearance. Neuron 96:827-838.e9. https://doi.org/10.1016/j.neuron.2017.09.038CrossRefPubMed

Schroeder CE, Metha AD, Givre SJ (1998) A spatiotemporal profile of visual system activation revealed by current source density analysis in the awake macaque. Cereb Cortex 8:575–592CrossRef

Smalla KH, Matthies H, Langnäse K, Shabir S, Böckers TM, Wyneken U, Staak S, Krug M, Beesley PW, Gundelfinger ED (2000) The synaptic glycoprotein neuroplastin is involved in long-term potentiation at hippocampal CA1 synapses. Proc Natl Acad Sci USA 97:4327–4332. https://doi.org/10.1073/pnas.080389297CrossRefPubMed

Spoendlin H (1969) Innervation patterns in the organ of corti of the cat. Acta Otolaryngol 67:239–254CrossRef

Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M (2019) Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression. Mol Carcinog 58:980–995. https://doi.org/10.1002/mc.22987CrossRefPubMed

Suzuki J, Imanishi E, Nagata S (2016) Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure. Proc Natl Acad Sci USA 113:9509–9514. https://doi.org/10.1073/pnas.1610403113CrossRefPubMed

Thanos PK, Robison L, Nestler EJ, Kim R, Michaelides M, Lobo MK, Volkow ND (2013) Mapping brain metabolic connectivity in awake rats with μPET and optogenetic stimulation. J Neurosci 33:6343–6349. https://doi.org/10.1523/JNEUROSCI.4997-12.2013CrossRefPubMedPubMedCentral

Vemula SK, Malci A, Junge L, Lehmann AC, Rama R, Hradsky J, Matute RA, Weber A, Prigge M, Naumann M, Kreutz MR, Seidenbecher CI, Gundelfinger ED, Herrera-Molina R (2020) The interaction of TRAF6 with neuroplastin promotes spinogenesis during early neuronal development. Front Cell Dev Biol 8:579513. https://doi.org/10.3389/fcell.2020.579513CrossRefPubMedPubMedCentral

Vollmer M (2018) Neural processing of acoustic and electric interaural time differences in normal-hearing gerbils. J Neurosci 38:6949–6966CrossRef

Wiegner A, Wright CG, Vollmer M (2016) Multichannel cochlear implant for selective neuronal activation and chronic use in the free-moving Mongolian gerbil. J Neurosci Methods 273:40–54CrossRef

Wilson MC, Kraus M, Marzban H, Sarna JR, Wang Y, Hawkes R, Halestrap AP, Beesley PW (2013) The neuroplastin adhesion molecules are accessory proteins that chaperone the monocarboxylate transporter MCT2 to the neuronal cell surface. PLoS ONE 8:e78654. https://doi.org/10.1371/journal.pone.0078654CrossRefPubMedPubMedCentral

Wyckhuys T, Staelens S, Van Nieuwenhuyse B, Deleye S, Hallez H, Vonck K, Raedt R, Wadman W, Boon P (2010) Hippocampal deep brain stimulation induces decreased rCBF in the hippocampal formation of the rat. Neuroimage 52:55–61. https://doi.org/10.1016/j.neuroimage.2010.04.017CrossRefPubMed

Yagi T, Asada R, Kanekura K, Eesmaa A, Lindahl M, Saarma M, Urano F (2020) Neuroplastin modulates anti-inflammatory effects of MANF. iScience 23:101810. https://doi.org/10.1016/j.isci.2020.101810CrossRefPubMedPubMedCentral

Zeng WZ, Grillet N, Dewey JB, Trouillet A, Krey JF, Barr-Gillespie PG, Oghalai JS, Müller U (2016) Neuroplastin isoform Np55 is expressed in the stereocilia of outer hair cells and required for normal outer hair cell function. J Neurosci 36:9201–9216. https://doi.org/10.1523/JNEUROSCI.0093-16.2016CrossRefPubMedPubMedCentral

Title: Neuroplastin expression is essential for hearing and hair cell PMCA expression
Authors: Xiao Lin
Michael G. K. Brunk
Pingan Yuanxiang
Andrew W. Curran
Enqi Zhang
Franziska Stöber
Jürgen Goldschmidt
Eckart D. Gundelfinger
Maike Vollmer
Max F. K. Happel
Rodrigo Herrera-Molina
Dirk Montag
Publication date: 01-06-2021
Publisher: Springer Berlin Heidelberg
Published in: Brain Structure and Function / Issue 5/2021
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-021-02269-w

At a glance: The STEP trials

Springer Medicine

Neuroplastin expression is essential for hearing and hair cell PMCA expression

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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