{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T06:36:01Z","timestamp":1775889361548,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:00:00Z","timestamp":1619395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Grantov\u00e1 Agentura \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["20-06927S"],"award-info":[{"award-number":["20-06927S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004240","name":"Akademie V\u011bd \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["86652036"],"award-info":[{"award-number":["86652036"]}],"id":[{"id":"10.13039\/501100004240","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA\/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.<\/jats:p>","DOI":"10.3390\/ijms22094507","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T02:31:43Z","timestamp":1619490703000},"page":"4507","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Overexpression of Isl1 under the Pax2 Promoter, Leads to Impaired Sound Processing and Increased Inhibition in the Inferior Colliculus"],"prefix":"10.3390","volume":"22","author":[{"given":"Tetyana","family":"Chumak","sequence":"first","affiliation":[{"name":"Institute of Experimental Medicine CAS, V\u00eddenska 1083, 14220 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Tothova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine CAS, V\u00eddenska 1083, 14220 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iva","family":"Filova","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology CAS, 25250 Vestec, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zbynek","family":"Bures","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine CAS, V\u00eddenska 1083, 14220 Prague, Czech Republic"},{"name":"Department of Technical Studies, The College of Polytechnics, 58601 Jihlava, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiri","family":"Popelar","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine CAS, V\u00eddenska 1083, 14220 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5689-6577","authenticated-orcid":false,"given":"Gabriela","family":"Pavlinkova","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology CAS, 25250 Vestec, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josef","family":"Syka","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine CAS, V\u00eddenska 1083, 14220 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.heares.2018.01.008","article-title":"Subcortical pathways: Towards a better understanding of auditory disorders","volume":"362","author":"Felix","year":"2018","journal-title":"Hear. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8952","DOI":"10.1523\/JNEUROSCI.0745-17.2017","article-title":"Identified GABAergic and Glutamatergic Neurons in the Mouse Inferior Colliculus Share Similar Response Properties","volume":"37","author":"Ono","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0304-3940(84)90557-3","article-title":"Inferior colliculus in the rat: Neuronal responses to stimulation of the auditory cortex","volume":"51","author":"Syka","year":"1984","journal-title":"Neurosci. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/cne.901960104","article-title":"The representation of the auditory and somatosensory systems in the external nucleus of the cat inferior colliculus","volume":"196","author":"Aitkin","year":"1981","journal-title":"J. Comp. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.neuroscience.2004.12.030","article-title":"The inferior colliculus of the rat: Quantitative immunocytochemical study of GABA and glycine","volume":"136","author":"Merchan","year":"2005","journal-title":"Neuroscience"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/cne.903400104","article-title":"Morphology of GABAergic neurons in the inferior colliculus of the cat","volume":"340","author":"Oliver","year":"1994","journal-title":"J. Comp. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s00441-014-2107-2","article-title":"Age-related changes in the central auditory system","volume":"361","author":"Ouda","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fncir.2012.00068","article-title":"Immunocytochemical profiles of inferior colliculus neurons in the rat and their changes with aging","volume":"6","author":"Ouda","year":"2012","journal-title":"Front. Neural Circuits"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.heares.2019.02.005","article-title":"Morphological and neurochemical changes in GABAergic neurons of the aging human inferior colliculus","volume":"377","author":"Pal","year":"2019","journal-title":"Hear. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ono, M., and Ito, T. (2018). Inhibitory Neural Circuits in the Mammalian Auditory Midbrain. J. Exp. Neurosci., 12.","DOI":"10.1177\/1179069518818230"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0092-8674(00)80985-X","article-title":"Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation","volume":"84","author":"Pfaff","year":"1996","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1038\/nn.2209","article-title":"A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs","volume":"11","author":"Sun","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.ydbio.2006.03.053","article-title":"Isl1 is upstream of sonic hedgehog in a pathway required for cardiac morphogenesis","volume":"295","author":"Lin","year":"2006","journal-title":"Dev. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/S1534-5807(03)00363-0","article-title":"Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart","volume":"5","author":"Cai","year":"2003","journal-title":"Dev. Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12707","DOI":"10.1523\/JNEUROSCI.3951-07.2007","article-title":"Islet-1 controls the differentiation of retinal bipolar and cholinergic amacrine cells","volume":"27","author":"Elshatory","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9697","DOI":"10.1073\/pnas.1103253108","article-title":"Genetic modulation of horizontal cell number in the mouse retina","volume":"108","author":"Whitney","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0168-9525(99)01883-1","article-title":"Functions of LIM-homeobox genes","volume":"16","author":"Hobert","year":"2000","journal-title":"Trends Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1242\/dev.129.2.307","article-title":"The activation and maintenance of Pax2 expression at the mid-hindbrain boundary is controlled by separate enhancers","volume":"129","author":"Pfeffer","year":"2002","journal-title":"Development"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13870","DOI":"10.1073\/pnas.93.24.13870","article-title":"The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney","volume":"93","author":"Favor","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bouchard, M., de Caprona, D., Busslinger, M., Xu, P., and Fritzsch, B. (2010). Pax2 and Pax8 cooperate in mouse inner ear morphogenesis and innervation. BMC Dev. Biol., 10.","DOI":"10.1186\/1471-213X-10-89"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1007\/s12035-015-9215-1","article-title":"Deterioration of the Medial Olivocochlear Efferent System Accelerates Age-Related Hearing Loss in Pax2-Isl1 Transgenic Mice","volume":"53","author":"Chumak","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1007\/s12035-016-9716-6","article-title":"Pax2-Islet1 Transgenic Mice Are Hyperactive and Have Altered Cerebellar Foliation","volume":"54","author":"Bohuslavova","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.brainres.2006.01.107","article-title":"Auditory brainstem responses in 10 inbred strains of mice","volume":"1091","author":"Zhou","year":"2006","journal-title":"Brain Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/S0378-5955(99)00003-9","article-title":"Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses","volume":"130","author":"Zheng","year":"1999","journal-title":"Hear. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/0378-5955(95)00179-4","article-title":"Generators of the brainstem auditory evoked potential in cat. II. Correlating lesion sites with waveform changes","volume":"93","author":"Melcher","year":"1996","journal-title":"Hear. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.heares.2016.08.008","article-title":"The contribution of inferior colliculus activity to the auditory brainstem response (ABR) in mice","volume":"341","author":"Land","year":"2016","journal-title":"Hear. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.heares.2007.10.002","article-title":"First spike latency and spike count as functions of tone amplitude and frequency in the inferior colliculus of mice","volume":"235","author":"Tan","year":"2008","journal-title":"Hear. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5607","DOI":"10.1007\/s12035-015-9474-x","article-title":"BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury","volume":"53","author":"Chumak","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.neuron.2011.11.035","article-title":"The Generation of Direction Selectivity in the Auditory System","volume":"73","author":"Kuo","year":"2012","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.heares.2010.05.010","article-title":"The dominance of inhibition in the inferior colliculus","volume":"274","author":"Pollak","year":"2011","journal-title":"Hear. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0304-3940(98)00911-2","article-title":"Sound stimulation increases calcium-binding protein immunoreactivity in the inferior colliculus in mice","volume":"259","author":"Idrizbegovic","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s00221-009-1776-7","article-title":"Neuronal subtype identity in the rat auditory brainstem as defined by molecular profile and axonal projection","volume":"195","author":"Fredrich","year":"2009","journal-title":"Exp. Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4019","DOI":"10.1152\/jn.00688.2005","article-title":"Differing roles of inhibition in hierarchical processing of species-specific calls in auditory brainstem nuclei","volume":"94","author":"Xie","year":"2005","journal-title":"J. Neurophysiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1152\/jn.00956.2004","article-title":"Role of GABAergic inhibition in the coding of interaural time differences of low-frequency sounds in the inferior colliculus","volume":"93","author":"Sterbing","year":"2005","journal-title":"J. Neurophysiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4003","DOI":"10.1113\/jphysiol.2013.255943","article-title":"Classification of frequency response areas in the inferior colliculus reveals continua not discrete classes","volume":"591","author":"Palmer","year":"2013","journal-title":"J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1007\/s00221-006-0424-8","article-title":"Inhibitory and excitatory response areas of neurons in the central nucleus of the inferior colliculus in unanesthetized chinchillas","volume":"174","author":"Alkhatib","year":"2006","journal-title":"Exp. Brain Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s002210100786","article-title":"Frequency response areas of neurons in the mouse inferior colliculus. I. Threshold and tuning characteristics","volume":"140","author":"Egorova","year":"2001","journal-title":"Exp. Brain Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1152\/jn.1996.75.2.902","article-title":"Contribution of GABA- and glycine-mediated inhibition to the monaural temporal response properties of neurons in the inferior colliculus","volume":"75","author":"Rees","year":"1996","journal-title":"J. Neurophysiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7303","DOI":"10.1523\/JNEUROSCI.21-18-07303.2001","article-title":"Iontophoresis in vivo demonstrates a key role for GABA(A) and glycinergic inhibition in shaping frequency response areas in the inferior colliculus of guinea pig","volume":"21","author":"LeBeau","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1152\/jn.1992.68.5.1760","article-title":"GABAergic circuits sharpen tuning curves and modify response properties in the mustache bat inferior colliculus","volume":"68","author":"Yang","year":"1992","journal-title":"J. Neurophysiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.1152\/jn.00569.2011","article-title":"Differential roles of GABAergic and glycinergic input on FM selectivity in the inferior colliculus of the pallid bat","volume":"106","author":"Williams","year":"2011","journal-title":"J. Neurophysiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5172","DOI":"10.1523\/JNEUROSCI.13-12-05172.1993","article-title":"GABA shapes a topographic organization of response latency in the mustache bat\u2019s inferior colliculus","volume":"13","author":"Park","year":"1993","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1152\/jn.1996.75.6.2211","article-title":"GABA inputs control discharge rate primarily within frequency receptive fields of inferior colliculus neurons","volume":"75","author":"Palombi","year":"1996","journal-title":"J. Neurophysiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"174","DOI":"10.3389\/fncir.2013.00174","article-title":"Midbrain local circuits shape sound intensity codes","volume":"7","author":"Grimsley","year":"2013","journal-title":"Front. Neural Circuit"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/BF00318606","article-title":"Calcium-binding proteins: Selective markers of nerve cells","volume":"271","author":"Andressen","year":"1993","journal-title":"Cell Tissue Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/0166-2236(92)90081-I","article-title":"Calcium-binding proteins in the nervous system","volume":"15","author":"Baimbridge","year":"1992","journal-title":"Trends Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1002\/cne.10676","article-title":"Upregulation of calretinin immunostaining in the ferret inferior colliculus after cochlear ablation","volume":"460","author":"Alvarado","year":"2003","journal-title":"J. Comp. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3674","DOI":"10.1111\/ejn.12732","article-title":"Acoustical enrichment during early postnatal development changes response properties of inferior colliculus neurons in rats","volume":"40","author":"Bures","year":"2014","journal-title":"Eur. J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1111\/j.1460-9568.2009.06739.x","article-title":"Brief exposure of juvenile rats to noise impairs the development of the response properties of inferior colliculus neurons","volume":"29","author":"Grecova","year":"2009","journal-title":"Eur. J. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5903720","DOI":"10.1155\/2018\/5903720","article-title":"Acoustical Enrichment during Early Development Improves Response Reliability in the Adult Auditory Cortex of the Rat","volume":"2018","author":"Bures","year":"2018","journal-title":"Neural Plast."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1523\/JNEUROSCI.3088-09.2010","article-title":"Synaptic mechanisms of direction selectivity in primary auditory cortex","volume":"30","author":"Ye","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_52","unstructured":"Paxinos, G., and Franklin, K.B.J. (2001). The Mouse Brain in Stereotaxic Coordinates, Academic Press. [2nd ed.]."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.yjmcc.2013.04.015","article-title":"Increased susceptibility of HIF-1alpha heterozygous-null mice to cardiovascular malformations associated with maternal diabetes","volume":"60","author":"Bohuslavova","year":"2013","journal-title":"J. Mol. Cell Cardiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4507\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:52:55Z","timestamp":1760161975000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4507"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,26]]},"references-count":53,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22094507"],"URL":"https:\/\/doi.org\/10.3390\/ijms22094507","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,26]]}}}