{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T19:03:23Z","timestamp":1783191803714,"version":"3.54.6"},"reference-count":40,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Croatian Science Foundation","award":["IP-2019-04-3182"],"award-info":[{"award-number":["IP-2019-04-3182"]}]},{"name":"The Croatian Science Foundation","award":["10106-22-3116"],"award-info":[{"award-number":["10106-22-3116"]}]},{"name":"European Regional Development Fund","award":["IP-2019-04-3182"],"award-info":[{"award-number":["IP-2019-04-3182"]}]},{"name":"European Regional Development Fund","award":["10106-22-3116"],"award-info":[{"award-number":["10106-22-3116"]}]},{"name":"University of Zagreb","award":["IP-2019-04-3182"],"award-info":[{"award-number":["IP-2019-04-3182"]}]},{"name":"University of Zagreb","award":["10106-22-3116"],"award-info":[{"award-number":["10106-22-3116"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate the ECM profile of HS1 in surgically treated drug-resistant patients with MTLE in correlation to clinical findings. Hippocampal sections were immunohistochemically stained for aggrecan, neurocan, versican, chondroitin-sulfate (CS56), fibronectin, Wisteria floribunda agglutinin (WFA), a nuclear neuronal marker (NeuN), parvalbumin (PV), and glial-fibrillary-acidic-protein (GFAP). In HS1, besides the reduced number of neurons and astrogliosis, we found a significantly changed expression pattern of versican, neurocan, aggrecan, WFA-specific glycosylation, and a reduced number of PNNs. Patients with a lower number of epileptic episodes had a less intense diffuse WFA staining in Cornu Ammonis (CA) fields. Our findings suggest that PNN reduction, changed ECM protein, and glycosylation expression pattern in HS1 might be involved in the pathogenesis and persistence of drug-resistant MTLE by contributing to the increase of CA pyramidal neurons\u2019 excitability. This research corroborates the validity of ECM molecules and their modulators as a potential target for the development of new therapeutic approaches to drug-resistant epilepsy.<\/jats:p>","DOI":"10.3390\/ijms23158197","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T21:20:59Z","timestamp":1658784059000},"page":"8197","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Reorganization of the Brain Extracellular Matrix in Hippocampal Sclerosis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7085-5950","authenticated-orcid":false,"given":"Barbara","family":"Sita\u0161","sequence":"first","affiliation":[{"name":"Department of Neurology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1588-7658","authenticated-orcid":false,"given":"Mihaela","family":"Bobi\u0107-Rasonja","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Croatian Institute for Brain Research, Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goran","family":"Mrak","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7737-0622","authenticated-orcid":false,"given":"Sara","family":"Trnski","sequence":"additional","affiliation":[{"name":"Croatian Institute for Brain Research, Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Krbot Skori\u0107","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3018-5248","authenticated-orcid":false,"given":"Darko","family":"Ore\u0161kovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Clinical Hospital Dubrava, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinka","family":"Knezovi\u0107","sequence":"additional","affiliation":[{"name":"Croatian Institute for Brain Research, Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Anatomy and Clinical Anatomy, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u017deljka","family":"Petelin Gad\u017ee","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"},{"name":"Referral Centre of the Ministry of Health of the Republic of Croatia for Epilepsy, Affiliated Partner of the ERN EpiCARE, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5019-4198","authenticated-orcid":false,"given":"Zdravko","family":"Petanjek","sequence":"additional","affiliation":[{"name":"Croatian Institute for Brain Research, Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Anatomy and Clinical Anatomy, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6339-9261","authenticated-orcid":false,"given":"Goran","family":"\u0160imi\u0107","sequence":"additional","affiliation":[{"name":"Croatian Institute for Brain Research, Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department for Neuroscience, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danijela","family":"Kolenc","sequence":"additional","affiliation":[{"name":"Lucerne Cantonal Hospital, Institute of Pathology, 6006 Lucerne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7897-6212","authenticated-orcid":false,"given":"Nata\u0161a","family":"Jovanov Milo\u0161evi\u0107","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Croatian Institute for Brain Research, Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,25]]},"reference":[{"key":"ref_1","unstructured":"Engel, J.J., and Pedley, T. (1997). Mesial Temporal Lobe Epilepsy. Epilepsy: A Comprehensive Textbook, Lippincott-Raven."},{"key":"ref_2","unstructured":"Engel, J.J., and Pedley, T. (1997). Hippocampal Sclerosis. Epilepsy: A Comprehensive Textbook, Lippincott-Raven."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1177\/107385840100700410","article-title":"Mesial Temporal Lobe Epilepsy: What Have We Learned?","volume":"7","author":"Engel","year":"2001","journal-title":"Neuroscientist"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/nan.12150","article-title":"Review: Hippocampal Sclerosis in Epilepsy: A Neuropathology Review","volume":"40","author":"Thom","year":"2014","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/j.1528-1167.2010.02612.x","article-title":"Remodeling of Extracellular Matrix and Epileptogenesis","volume":"51","author":"Dityatev","year":"2010","journal-title":"Epilepsia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1080\/01926230701748305","article-title":"Mesial Temporal Lobe Epilepsy: Pathogenesis, Induced Rodent Models and Lesions","volume":"35","author":"Sharma","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.yebeh.2008.09.023","article-title":"Molecular and Cellular Basis of Epileptogenesis in Symptomatic Epilepsy","volume":"14","author":"Lukasiuk","year":"2009","journal-title":"Epilepsy Behav."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/j.neuint.2012.08.007","article-title":"The Perineuronal Net Component of the Extracellular Matrix in Plasticity and Epilepsy","volume":"61","author":"McRae","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"270","DOI":"10.3389\/fnmol.2018.00270","article-title":"The Perineuronal \u2018Safety\u2019 Net? Perineuronal Net Abnormalities in Neurological Disorders","volume":"11","author":"Wen","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.neuroscience.2013.08.050","article-title":"Targeting the Neural Extracellular Matrix in Neurological Disorders","volume":"253","author":"Soleman","year":"2013","journal-title":"Neuroscience"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/nrn2898","article-title":"The Dual Role of the Extracellular Matrix in Synaptic Plasticity and Homeostasis","volume":"11","author":"Dityatev","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1054\/jocn.1999.0212","article-title":"Extracellular Matrix and the Brain: Components and Function","volume":"7","author":"Novak","year":"2000","journal-title":"J. Clin. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/s00418-008-0485-9","article-title":"Extracellular Matrix of the Central Nervous System: From Neglect to Challenge","volume":"130","author":"Zimmermann","year":"2008","journal-title":"Histochem. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1007\/s00018-004-4043-x","article-title":"Extracellular Matrix Components Associated with Remodeling Processes in Brain","volume":"61","author":"Rauch","year":"2004","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1006\/exnr.1997.6469","article-title":"Correlated Axonal Sprouting and Dendritic Spine Formation during Kainate-Induced Neuronal Morphogenesis in the Dentate Gyrus of Adult Mice","volume":"145","author":"Suzuki","year":"1997","journal-title":"Exp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41583-019-0196-3","article-title":"The Roles of Perineuronal Nets and the Perinodal Extracellular Matrix in Neuronal Function","volume":"20","author":"Fawcett","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.1111\/j.1460-9568.2012.08268.x","article-title":"Persistent Decrease in Multiple Components of the Perineuronal Net Following Status Epilepticus","volume":"36","author":"McRae","year":"2012","journal-title":"Eur. J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9847696","DOI":"10.1155\/2016\/9847696","article-title":"In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders","volume":"2016","author":"Pantazopoulos","year":"2016","journal-title":"Neural Plast."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1017\/S1740925X09000118","article-title":"Extracellular Matrix in Plasticity and Epileptogenesis","volume":"4","author":"Dityatev","year":"2008","journal-title":"Neuron Glia Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fnana.2018.00040","article-title":"Shaping Synapses by the Neural Extracellular Matrix","volume":"12","author":"Dityatev","year":"2018","journal-title":"Front. Neuroanat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1111\/epi.13026","article-title":"Perineuronal Net Degradation in Epilepsy","volume":"56","author":"McRae","year":"2015","journal-title":"Epilepsia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1146\/annurev-neuro-071714-034019","article-title":"Neurological Aspects of Human Glycosylation Disorders","volume":"38","author":"Freeze","year":"2015","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Carulli, D., and Verhaagen, J. (2021). An Extracellular Perspective on CNS Maturation: Perineuronal Nets and the Control of Plasticity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052434"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00401-009-0619-8","article-title":"V Astrocytes: Biology and Pathology","volume":"119","author":"Sofroniew","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5446","DOI":"10.1007\/s12035-015-9465-y","article-title":"The Severity of Gliosis in Hippocampal Sclerosis Correlates with Pre-Operative Seizure Burden and Outcome After Temporal Lobectomy","volume":"53","author":"Johnson","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.neuroscience.2012.06.002","article-title":"Hippocampal Tissue of Patients with Refractory Temporal Lobe Epilepsy Is Associated with Astrocyte Activation, Inflammation, and Altered Expression of Channels and Receptors","volume":"220","author":"Das","year":"2012","journal-title":"Neuroscience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7742","DOI":"10.1523\/JNEUROSCI.3275-12.2013","article-title":"Primary Hippocampal Neurons, Which Lack Four Crucial Extracellular Matrix Molecules, Display Abnormalities of Synaptic Structure and Function and Severe Deficits in Perineuronal Net Formation","volume":"33","author":"Geissler","year":"2013","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.neuroscience.2018.05.039","article-title":"Normal Development of the Perineuronal Net in Humans; In Patients with and without Epilepsy","volume":"384","author":"Rogers","year":"2018","journal-title":"Neuroscience"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"53","DOI":"10.5698\/1535-7597.18.1.53","article-title":"Lost Inhibition-Brain Activity Temporarily Out of Control","volume":"18","author":"Gross","year":"2018","journal-title":"Epilepsy Curr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.neuroscience.2007.07.029","article-title":"Quantitative Analysis of Parvalbumin-Immunoreactive Cells in the Human Epileptic Hippocampus","volume":"149","author":"Andrioli","year":"2007","journal-title":"Neuroscience"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1093\/brain\/awh004","article-title":"Histopathology and Reorganization of Chandelier Cells in the Human Epileptic Sclerotic Hippocampus","volume":"127","author":"Arellano","year":"2004","journal-title":"Brain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/S0306-4522(01)00446-8","article-title":"Preservation of Perisomatic Inhibitory Input of Granule Cells in the Epileptic Human Dentate Gyrus","volume":"108","author":"Wittner","year":"2001","journal-title":"Neuroscience"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/cne.903080306","article-title":"Calcium-Binding Protein (Calbindin-D28K) and Parvalbumin Immunocytochemistry in the Normal and Epileptic Human Hippocampus","volume":"308","author":"Sloviter","year":"1991","journal-title":"J. Comp. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/0165-0173(94)90006-X","article-title":"Perineuronal Nets-a Specialized Form of Extracellular Matrix in the Adult Nervous System","volume":"19","author":"Celio","year":"1994","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4724","DOI":"10.1038\/s41467-018-07113-0","article-title":"Perineuronal Nets Decrease Membrane Capacitance of Peritumoral Fast Spiking Interneurons in a Model of Epilepsy","volume":"9","author":"Tewari","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_36","unstructured":"Petelin Gad\u017ee, \u017d. (2017). Dijagnosti\u010dki i Terapijski Pristup Bolesniku s Epilepsijom. Dijagnosti\u010dki i Terapijski Pristup Bolesniku s Epilepsijom, Medicinska Naklada."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1111\/j.1460-9568.2010.07400.x","article-title":"Morphology, Molecular Phenotypes and Distribution of Neurons in Developing Human Corpus Callosum","volume":"32","author":"Petanjek","year":"2010","journal-title":"Eur. J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1111\/joa.13011","article-title":"Callosal Septa Express Guidance Cues and Are Paramedian Guideposts for Human Corpus Callosum Development","volume":"235","author":"Culjat","year":"2019","journal-title":"J. Anat."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/s41467-021-27602-z","article-title":"Constitutive Activation of Canonical Wnt Signaling Disrupts Choroid Plexus Epithelial Fate","volume":"13","author":"Parichha","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8197\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:56:12Z","timestamp":1760140572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8197"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,25]]},"references-count":40,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23158197"],"URL":"https:\/\/doi.org\/10.3390\/ijms23158197","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,25]]}}}