Abstract
The α2δ3 auxiliary subunit of voltage-activated calcium channels is required for normal synaptic transmission and precise temporal processing of sounds in the auditory brainstem. In mice its loss additionally leads to an inability to distinguish amplitude-modulated tones. Furthermore, loss of function of α2δ3 has been associated with autism spectrum disorder in humans. To investigate possible alterations of network activity in the higher-order auditory system in α2δ3 knockout mice, we analyzed neuronal activity patterns and topography of frequency tuning within networks of the auditory cortex (AC) using two-photon Ca2+ imaging. Compared to wild-type mice we found distinct subfield-specific alterations in the primary auditory cortex, expressed in overall lower correlations between the network activity patterns in response to different sounds as well as lower reliability of these patterns upon repetitions of the same sound. Higher AC subfields did not display these alterations but showed a higher amount of well-tuned neurons along with lower local heterogeneity of the neurons’ frequency tuning. Our results provide new insight into AC network activity alterations in an autism spectrum disorder-associated mouse model.
Funding source: Deutsche Forschungsgemeinschaft
Award Identifier / Grant number: PP1608 (En 294/5-2 to JE, KU 1972/5-2 to SK) and SFB 894 (A8 to JE)
Funding source: BioComp Research Initiative
Acknowledgments
We thank Matthias Göttsche (Stocksee, Germany) for permitting the use of the recordings of the Blasius’s Horseshoe Bat. We thank Kerstin Fischer (Saarland University) and Kornelia Ociepka (University of Kaiserslautern) for excellent technical assistance.
-
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
-
Research funding: This work was supported by Deutsche Forschungsgemeinschaft (DFG) PP1608 (En 294/5-2 to JE, KU 1972/5-2 to SK) and DFG SFB 894 (A8 to JE). We thank the BioComp Research Initiative for funding.
-
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
References
Ablinger, C., Geisler, S.M., Stanika, R.I., Klein, C.T., and Obermair, G.J. (2020). Neuronal α(2)δ proteins and brain disorders. Pflüger‘s Arch. Eur. J. Physiol. 472: 845–863, https://doi.org/10.1007/s00424-020-02420-2.Suche in Google Scholar PubMed PubMed Central
Atiani, S., David, S.V., Elgueda, D., Locastro, M., Radtke-Schuller, S., Shamma, S.A., and Fritz, J.B. (2014). Emergent selectivity for task-relevant stimuli in higher-order auditory cortex. Neuron 82: 486–499, https://doi.org/10.1016/j.neuron.2014.02.029.Suche in Google Scholar PubMed PubMed Central
Bajo, V.M., Nodal, F.R., Moore, D.R., and King, A.J. (2010). The descending corticocollicular pathway mediates learning-induced auditory plasticity. Nat. Neurosci. 13: 253–260, https://doi.org/10.1038/nn.2466.Suche in Google Scholar PubMed PubMed Central
Bandyopadhyay, S., Shamma, S.A., and Kanold, P.O. (2010). Dichotomy of functional organization in the mouse auditory cortex. Nat. Neurosci. 13: 361–368, https://doi.org/10.1038/nn.2490.Suche in Google Scholar PubMed PubMed Central
Bathellier, B., Ushakova, L., and Rumpel, S. (2012). Discrete neocortical dynamics predict behavioral categorization of sounds. Neuron 76: 435–449, https://doi.org/10.1016/j.neuron.2012.07.008.Suche in Google Scholar PubMed
Bikbaev, A., Ciuraszkiewicz-Wojciech, A., Heck, J., Klatt, O., Freund, R., Mitlöhner, J., Enrile Lacalle, S., Sun, M., Repetto, D., Frischknecht, R., et al.. (2020). Auxiliary α2δ1 and α2δ3 subunits of calcium channels drive excitatory and inhibitory neuronal network development. J. Neurosci. 40: 4824–4841, https://doi.org/10.1523/jneurosci.1707-19.2020.Suche in Google Scholar PubMed PubMed Central
Bowen, Z., Winkowski, D.E., and Kanold, P.O. (2020). Functional organization of mouse primary auditory cortex in adult C57BL/6 and F1 (CBAxC57) mice. Sci. Rep. 10: 10905, https://doi.org/10.1038/s41598-020-67819-4.Suche in Google Scholar PubMed PubMed Central
Bracic, G., Hegmann, K., Engel, J., and Kurt, S. (2022). Impaired subcortical processing of amplitude-modulated tones in mice deficient for Cacna2d3, a risk gene for autism spectrum disorders in humans. eNeuro 9, https://doi.org/10.1523/eneuro.0118-22.2022.Suche in Google Scholar PubMed PubMed Central
Caras, M.L. and Sanes, D.H. (2017). Top-down modulation of sensory cortex gates perceptual learning. Proc. Natl. Acad. Sci. USA 114: 9972–9977, https://doi.org/10.1073/pnas.1712305114.Suche in Google Scholar PubMed PubMed Central
Cole, R.L., Lechner, S.M., Williams, M.E., Prodanovich, P., Bleicher, L., Varney, M.A., and Gu, G. (2005). Differential distribution of voltage-gated calcium channel alpha-2 delta (α2δ) subunit mRNA-containing cells in the rat central nervous system and the dorsal root ganglia. J. Comp. Neurol. 491: 246–269, https://doi.org/10.1002/cne.20693.Suche in Google Scholar PubMed
De Rubeis, S., He, X., Goldberg, A.P., Poultney, C.S., Samocha, K., Cicek, A.E., Kou, Y., Liu, L., Fromer, M., Walker, S., et al.. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515: 209–215, https://doi.org/10.1038/nature13772.Suche in Google Scholar PubMed PubMed Central
Dolphin, A.C. (2012). Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond. Nat. Rev. Neurosci. 13: 542, https://doi.org/10.1038/nrn3311.Suche in Google Scholar PubMed
Friedrich, J., Zhou, P., and Paninski, L. (2017). Fast online deconvolution of calcium imaging data. PLoS Comput. Biol. 13: e1005423, https://doi.org/10.1371/journal.pcbi.1005423.Suche in Google Scholar PubMed PubMed Central
Gaucher, Q., Panniello, M., Ivanov, A.Z., Dahmen, J.C., King, A.J., and Walker, K.M.M. (2020). Complexity of frequency receptive fields predicts tonotopic variability across species. eLife 9: e53462, https://doi.org/10.7554/elife.53462.Suche in Google Scholar PubMed PubMed Central
Geisler, S.M., Benedetti, A., Schöpf, C.L., Schwarzer, C., Stefanova, N., Schwartz, A., and Obermair, G.J. (2021). Phenotypic characterization and brain structure analysis of calcium channel subunit α2δ-2 mutant (ducky) and α2δ double knockout mice. Front. Synaptic Neurosci. 13: 634412, https://doi.org/10.3389/fnsyn.2021.634412.Suche in Google Scholar PubMed PubMed Central
Girirajan, S., Dennis Megan, Y., Baker, C., Malig, M., Coe Bradley, P., Campbell Catarina, D., Mark, K., Vu Tiffany, H., Alkan, C., Cheng, Z., et al.. (2013). Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am. J. Hum. Genet. 92: 221–237, https://doi.org/10.1016/j.ajhg.2012.12.016.Suche in Google Scholar PubMed PubMed Central
Guo, W., Chambers, A.R., Darrow, K.N., Hancock, K.E., Shinn-Cunningham, B.G., and Polley, D.B. (2012). Robustness of cortical topography across fields, laminae, anesthetic states, and neurophysiological signal types. J. Neurosci. 32: 9159–9172, https://doi.org/10.1523/jneurosci.0065-12.2012.Suche in Google Scholar PubMed PubMed Central
Homma, N.Y., Happel, M.F., Nodal, F.R., Ohl, F.W., King, A.J., and Bajo, V.M. (2017). A role for auditory corticothalamic feedback in the perception of complex sounds. J. Neurosci. 37: 6149–6161, https://doi.org/10.1523/jneurosci.0397-17.2017.Suche in Google Scholar PubMed PubMed Central
Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., Yamrom, B., Lee, Y.-H., Narzisi, G., Leotta, A., et al.. (2012). De novo gene disruptions in children on the autistic spectrum. Neuron 74: 285–299, https://doi.org/10.1016/j.neuron.2012.04.009.Suche in Google Scholar PubMed PubMed Central
Issa, J.B., Haeffele Benjamin, D., Agarwal, A., Bergles Dwight, E., Young Eric, D., and Yue David, T. (2014). Multiscale optical Ca2+ imaging of tonal organization in mouse auditory cortex. Neuron 83: 944–959, https://doi.org/10.1016/j.neuron.2014.07.009.Suche in Google Scholar PubMed PubMed Central
Joachimsthaler, B., Uhlmann, M., Miller, F., Ehret, G., and Kurt, S. (2014). Quantitative analysis of neuronal response properties in primary and higher-order auditory cortical fields of awake house mice (Mus musculus). Eur. J. Physiol. 39: 904–918, https://doi.org/10.1111/ejn.12478.Suche in Google Scholar PubMed PubMed Central
Keehn, B., Kadlaskar, G., McNally Keehn, R., and Francis, A.L. (2019). Auditory attentional disengagement in children with autism spectrum disorder. J. Autism Dev. Disord. 49: 3999–4008, https://doi.org/10.1007/s10803-019-04111-z.Suche in Google Scholar PubMed PubMed Central
Kim, H. and Bao, S. (2013). Experience-dependent overrepresentation of ultrasonic vocalization frequencies in the rat primary auditory cortex. J. Neurophysiol. 110: 1087–1096, https://doi.org/10.1152/jn.00230.2013.Suche in Google Scholar PubMed PubMed Central
Kim, H., Gibboni, R., Kirkhart, C., and Bao, S. (2013). Impaired critical period plasticity in primary auditory cortex of fragile X model mice. J. Neurosci. 33: 15686–15692, https://doi.org/10.1523/jneurosci.3246-12.2013.Suche in Google Scholar
Ko, H., Hofer, S.B., Pichler, B., Buchanan, K.A., Sjostrom, P.J., and Mrsic-Flogel, T.D. (2011). Functional specificity of local synaptic connections in neocortical networks. Nature 473: 87–91, https://doi.org/10.1038/nature09880.Suche in Google Scholar PubMed PubMed Central
Kurshan, P.T., Oztan, A., and Schwarz, T.L. (2009). Presynaptic alpha2delta-3 is required for synaptic morphogenesis independent of its Ca2+-channel functions. Nat. Neurosci. 12: 1415–1423, https://doi.org/10.1038/nn.2417.Suche in Google Scholar PubMed PubMed Central
Kwakye, L.D., Foss-Feig, J.H., Cascio, C.J., Stone, W.L., and Wallace, M.T. (2011). Altered auditory and multisensory temporal processing in autism spectrum disorders. Front. Integr. Neurosci. 4: 129, https://doi.org/10.3389/fnint.2010.00129.Suche in Google Scholar PubMed PubMed Central
Landmann, J., Richter, F., Classen, J., Richter, A., Penninger, J.M., and Bechmann, I. (2019). Behavioral phenotyping of calcium channel (CACN) subunit α2δ3 knockout mice: consequences of sensory cross-modal activation. Behav. Brain Res. 364: 393–402, https://doi.org/10.1016/j.bbr.2017.12.032.Suche in Google Scholar PubMed
Landmann, J., Richter, F., Oros-Peusquens, A.M., Shah, N.J., Classen, J., Neely, G.G., Richter, A., Penninger, J.M., and Bechmann, I. (2018). Neuroanatomy of pain-deficiency and cross-modal activation in calcium channel subunit (CACN) α2δ3 knockout mice. Brain Struct. Funct. 223: 111–130, https://doi.org/10.1007/s00429-017-1473-4.Suche in Google Scholar PubMed
Lee, K., Jung, Y., Vyas, Y., Skelton, I., Abraham, W.C., Hsueh, Y.P., and Montgomery, J.M. (2022). Dietary zinc supplementation rescues fear-based learning and synaptic function in the Tbr1+/- mouse model of autism spectrum disorders. Mol. Autism 13: 13, https://doi.org/10.1186/s13229-022-00494-6.Suche in Google Scholar PubMed PubMed Central
Liu, J. and Kanold, P.O. (2021). Diversity of receptive fields and sideband inhibition with complex thalamocortical and intracortical origin in L2/3 of mouse primary auditory cortex. J. Neurosci. 41: 3142–3162, https://doi.org/10.1523/jneurosci.1732-20.2021.Suche in Google Scholar PubMed PubMed Central
Montes-Lourido, P., Kar, M., David, S.V., and Sadagopan, S. (2021). Neuronal selectivity to complex vocalization features emerges in the superficial layers of primary auditory cortex. PLoS Biol. 19: e3001299, https://doi.org/10.1371/journal.pbio.3001299.Suche in Google Scholar PubMed PubMed Central
Moore, A.K. and Wehr, M. (2013). Parvalbumin-expressing inhibitory interneurons in auditory cortex are well-tuned for frequency. J. Neurosci. 33: 13713–13723, https://doi.org/10.1523/jneurosci.0663-13.2013.Suche in Google Scholar
Moore, J.M. and Woolley, S.M.N. (2019). Emergent tuning for learned vocalizations in auditory cortex. Nat. Neurosci. 22: 1469–1476, https://doi.org/10.1038/s41593-019-0458-4.Suche in Google Scholar PubMed PubMed Central
Neely, G.G., Hess, A., Costigan, M., Keene, A.C., Goulas, S., Langeslag, M., Griffin, R.S., Belfer, I., Dai, F., Smith, S.B., et al.. (2010). A genome-wide Drosophila screen for heat nociception identifies α2δ3 as an evolutionarily conserved pain gene. Cell 143: 628–638, https://doi.org/10.1016/j.cell.2010.09.047.Suche in Google Scholar PubMed PubMed Central
O’Sullivan, C., Weible, A.P., and Wehr, M. (2019). Auditory cortex contributes to discrimination of pure tones. eNeuro 6, https://doi.org/10.1523/eneuro.0340-19.2019.Suche in Google Scholar
Ohl, F.W., Wetzel, W., Wagner, T., Rech, A., and Scheich, H. (1999). Bilateral ablation of auditory cortex in Mongolian gerbil affects discrimination of frequency modulated tones but not of pure tones. Learn. Mem. 6: 347–362, https://doi.org/10.1101/lm.6.4.347.Suche in Google Scholar
Ono, K., Kudoh, M., and Shibuki, K. (2006). Roles of the auditory cortex in discrimination learning by rats. Eur. J. Physiol. 23: 1623–1632, https://doi.org/10.1111/j.1460-9568.2006.04695.x.Suche in Google Scholar PubMed
Pachitariu, M., Stringer, C., Dipoppa, M., Schröder, S., Rossi, L.F., Dalgleish, H., Carandini, M., and Harris, K.D. (2017). Suite2p: beyond 10, 000 neurons with standard two-photon microscopy. bioRxiv: 061507.10.1101/061507Suche in Google Scholar
Panniello, M., King, A.J., Dahmen, J.C., and Walker, K.M.M. (2018). Local and global spatial organization of interaural level difference and frequency preferences in auditory cortex. Cereb. Cortex 28: 350–369, https://doi.org/10.1093/cercor/bhx295.Suche in Google Scholar PubMed PubMed Central
Pardi, M.B., Vogenstahl, J., Dalmay, T., Spanò, T., Pu, D.-L., Naumann, L.B., Kretschmer, F., Sprekeler, H., and Letzkus, J.J. (2020). A thalamocortical top-down circuit for associative memory. Science 370: 844–848, https://doi.org/10.1126/science.abc2399.Suche in Google Scholar PubMed
Pirone, A., Kurt, S., Zuccotti, A., Rüttiger, L., Pilz, P., Brown, D.H., Franz, C., Schweizer, M., Rust, M.B., Rübsamen, R., et al.. (2014). α2δ3 is essential for normal structure and function of auditory nerve synapses and is a novel candidate for auditory processing disorders. J. Neurosci. 34: 434–445, https://doi.org/10.1523/jneurosci.3085-13.2014.Suche in Google Scholar
Reinhard, S.M., Rais, M., Afroz, S., Hanania, Y., Pendi, K., Espinoza, K., Rosenthal, R., Binder, D.K., Ethell, I.M., and Razak, K.A. (2019). Reduced perineuronal net expression in Fmr1 KO mice auditory cortex and amygdala is linked to impaired fear-associated memory. Neurobiol. Learn. Mem. 164: 107042, https://doi.org/10.1016/j.nlm.2019.107042.Suche in Google Scholar PubMed PubMed Central
Rendall, A.R., Perrino, P.A., Buscarello, A.N., and Fitch, R.H. (2019). Shank3B mutant mice display pitch discrimination enhancements and learning deficits. Int. J. Dev. Neurosci. 72: 13–21, https://doi.org/10.1016/j.ijdevneu.2018.10.003.Suche in Google Scholar PubMed
Robertson, C.E. and Baron-Cohen, S. (2017). Sensory perception in autism. Nat. Rev. Neurosci. 18: 671, https://doi.org/10.1038/nrn.2017.112.Suche in Google Scholar PubMed
Romero, S., Hight, A.E., Clayton, K.K., Resnik, J., Williamson, R.S., Hancock, K.E., and Polley, D.B. (2019). Cellular and widefield imaging of sound frequency organization in primary and higher order fields of the mouse auditory cortex. Cereb. Cortex 30: 1603–1622, https://doi.org/10.1093/cercor/bhz190.Suche in Google Scholar PubMed PubMed Central
Rothschild, G., Nelken, I., and Mizrahi, A. (2010). Functional organization and population dynamics in the mouse primary auditory cortex. Nat. Neurosci. 13: 353–360, https://doi.org/10.1038/nn.2484.Suche in Google Scholar PubMed
Schafer, E.C., Mathews, L., Gopal, K., Canale, E., Creech, A., Manning, J., and Kaiser, K. (2020). Behavioral auditory processing in children and young adults with autism spectrum disorder. Am. J. Audiol. 31: 680–689, https://doi.org/10.1055/s-0040-1717138.Suche in Google Scholar PubMed
Schneider, D.M., Sundararajan, J., and Mooney, R. (2018). A cortical filter that learns to suppress the acoustic consequences of movement. Nature 561: 391–395, https://doi.org/10.1038/s41586-018-0520-5.Suche in Google Scholar PubMed PubMed Central
Schöpf, C.L., Ablinger, C., Geisler, S.M., Stanika, R.I., Campiglio, M., Kaufmann, W.A., Nimmervoll, B., Schlick, B., Brockhaus, J., Missler, M., et al.. (2021). Presynaptic α2δ subunits are key organizers of glutamatergic synapses. Proc. Natl. Acad. Sci. USA 118: e1920827118, https://doi.org/10.1073/pnas.1920827118.Suche in Google Scholar PubMed PubMed Central
Schulze, H., Deutscher, A., Tziridis, K., and Scheich, H. (2014). Unilateral auditory cortex lesions impair or improve discrimination learning of amplitude modulated sounds, depending on lesion side. PLoS One 9: e87159, https://doi.org/10.1371/journal.pone.0087159.Suche in Google Scholar PubMed PubMed Central
Stephani, F., Scheuer, V., Eckrich, T., Blum, K., Wang, W., Obermair, G.J., and Engel, J. (2019). Deletion of the Ca2+ channel subunit α2δ3 differentially affects cav2.1 and cav2.2 currents in cultured spiral ganglion neurons before and after the onset of hearing. Front. Cell. Neurosci. 13: 278, https://doi.org/10.3389/fncel.2019.00278.Suche in Google Scholar PubMed PubMed Central
Talwar, S.K., Musial, P.G., and Gerstein, G.L. (2001). Role of mammalian auditory cortex in the perception of elementary sound properties. J. Neurophysiol. 85: 2350–2358, https://doi.org/10.1152/jn.2001.85.6.2350.Suche in Google Scholar PubMed
Tasaka, G.-I., Guenthner, C.J., Shalev, A., Gilday, O., Luo, L., and Mizrahi, A. (2018). Genetic tagging of active neurons in auditory cortex reveals maternal plasticity of coding ultrasonic vocalizations. Nat. Commun. 9: 871, https://doi.org/10.1038/s41467-018-03183-2.Suche in Google Scholar PubMed PubMed Central
Tischbirek, C.H., Noda, T., Tohmi, M., Birkner, A., Nelken, I., and Konnerth, A. (2019). In vivo functional mapping of a cortical column at single-neuron resolution. Cell Rep. 27: 1319–1326.e1315, https://doi.org/10.1016/j.celrep.2019.04.007.Suche in Google Scholar PubMed
Vlaskamp, C., Oranje, B., Madsen, G.F., Møllegaard Jepsen, J.R., Durston, S., Cantio, C., Glenthøj, B., and Bilenberg, N. (2017). Auditory processing in autism spectrum disorder: mismatch negativity deficits. Autism Res. 10: 1857–1865, https://doi.org/10.1002/aur.1821.Suche in Google Scholar PubMed
Wetzel, W., Ohl, F.W., and Scheich, H. (2008). Global versus local processing of frequency-modulated tones in gerbils: an animal model of lateralized auditory cortex functions. Proc. Natl. Acad. Sci. USA 105: 6753–6758, https://doi.org/10.1073/pnas.0707844105.Suche in Google Scholar PubMed PubMed Central
Xin, Y., Zhong, L., Zhang, Y., Zhou, T., Pan, J., and Xu, N.-L. (2019). Sensory-to-Category transformation via dynamic reorganization of ensemble structures in mouse auditory cortex. Neuron 103: 909–921, https://doi.org/10.1016/j.neuron.2019.06.004.Suche in Google Scholar PubMed
Yang, S., Yang, S., Park, J.-S., Kirkwood, A., and Bao, S. (2014). Failed stabilization for long-term potentiation in the auditory cortex of FMR1 knockout mice. PLoS One 9: e104691, https://doi.org/10.1371/journal.pone.0104691.Suche in Google Scholar PubMed PubMed Central
Zhu, S., Allitt, B., Samuel, A., Lui, L., Rosa, M.G.P., and Rajan, R. (2019). Distributed representation of vocalization pitch in marmoset primary auditory cortex. Eur. J. Neurosci. 49: 179–198, https://doi.org/10.1111/ejn.14204.Suche in Google Scholar PubMed
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2022-0269).
© 2022 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Reviews
- Unravelling the genetic links between Parkinson’s disease and lung cancer
- Small-molecule metabolites in SARS-CoV-2 treatment: a comprehensive review
- Research Articles/Short Communications
- Molecular Medicine
- Dynamic regulation of eEF1A1 acetylation affects colorectal carcinogenesis
- New lipophilic organic nitrates: candidates for chronic skin disease therapy
- Cell Biology and Signaling
- Altered population activity and local tuning heterogeneity in auditory cortex of Cacna2d3-deficient mice
- Inhibition of miR-143-3p alleviates myocardial ischemia reperfusion injury via limiting mitochondria-mediated apoptosis
- Proteolysis
- The Mycobacterium tuberculosis prolyl dipeptidyl peptidase cleaves the N-terminal peptide of the immunoprotein CXCL-10
Artikel in diesem Heft
- Frontmatter
- Reviews
- Unravelling the genetic links between Parkinson’s disease and lung cancer
- Small-molecule metabolites in SARS-CoV-2 treatment: a comprehensive review
- Research Articles/Short Communications
- Molecular Medicine
- Dynamic regulation of eEF1A1 acetylation affects colorectal carcinogenesis
- New lipophilic organic nitrates: candidates for chronic skin disease therapy
- Cell Biology and Signaling
- Altered population activity and local tuning heterogeneity in auditory cortex of Cacna2d3-deficient mice
- Inhibition of miR-143-3p alleviates myocardial ischemia reperfusion injury via limiting mitochondria-mediated apoptosis
- Proteolysis
- The Mycobacterium tuberculosis prolyl dipeptidyl peptidase cleaves the N-terminal peptide of the immunoprotein CXCL-10