{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:22:30Z","timestamp":1785410550225,"version":"3.56.0"},"posted":{"date-parts":[[2025,8,13]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["4021"],"award-info":[{"award-number":["4021"]}],"id":[{"id":"https:\/\/ror.org\/00e7vz537","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["1R01NS106285"],"award-info":[{"award-number":["1R01NS106285"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Rett syndrome (RTT), caused by mutations in\n                  <jats:italic>MECP2<\/jats:italic>\n                  , is a complex neurological disorder characterized by myriad physiological disruptions, including early closure of the critical period of developmental plasticity and precocious formation of perineuronal nets (PNNs). PNNs are lattice-like substructures of extracellular matrix (ECM) that enwrap specific subpopulations of neurons. PNNs are essential in the modulation of neuronal plasticity and brain maturation, and their enzymatic disruption can partially restore plasticity in adults and improve memory. Although precocious PNN formation is well-established in RTT, little is known of the cellular, molecular, or biochemical underpinnings of their precocious formation, or whether precocious PNN formation is due to cell-autonomous or non-cell-autonomous mechanisms. While PNNs form on subsets of neurons throughout the brain, astrocytes secrete many ECM components that form PNNs, and they play a central role in controlling closure of the critical period. We find that\n                  <jats:italic>Mecp2<\/jats:italic>\n                  -null astrocyte conditioned media induces the expression of the key PNN component\n                  <jats:italic>Hapln1<\/jats:italic>\n                  and causes enhanced PNN formation on wildtype neurons, suggesting that\n                  <jats:italic>Mecp2<\/jats:italic>\n                  -null astrocytes play a key role in the precocious formation of PNNs in RTT. Further, we identify increased expression of HAPLN1 and other PNN \/ ECM components in the developing\n                  <jats:italic>Mecp2<\/jats:italic>\n                  -null cortex, and demonstrate that PNNs are structurally and biochemically mature at an earlier developmental stage. These results provide essential insight into the mechanisms and structure of aberrant PNNs in\n                  <jats:italic>Mecp2<\/jats:italic>\n                  -null cortex and identify potential new avenues for targeted rescue or reversal of the precocious closing of the critical period in RTT.\n                <\/jats:p>","DOI":"10.1101\/2025.08.13.670146","type":"posted-content","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T07:50:10Z","timestamp":1755157810000},"source":"Crossref","is-referenced-by-count":1,"title":["Astrocytic Regulation of aberrant perineuronal net formation in\n                  <i>Mecp2<\/i>\n                  -null Neocortex"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9028-0759","authenticated-orcid":false,"given":"Ashis","family":"Sinha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1331-2321","authenticated-orcid":false,"given":"Angelica M.","family":"Kowalchuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8030-550X","authenticated-orcid":false,"given":"Nasim","family":"Khatibi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-4215","authenticated-orcid":false,"given":"Russell T.","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9111-5756","authenticated-orcid":false,"given":"Jessica L.","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025081611100845000_2025.08.13.670146v1.1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4225-08.2009"},{"key":"2025081611100845000_2025.08.13.670146v1.2","doi-asserted-by":"crossref","first-page":"109296","DOI":"10.1016\/j.isci.2024.109296","article-title":"Mecp2 knock-out astrocytes affect synaptogenesis by interleukin 6 dependent mechanisms","volume":"27","year":"2024","journal-title":"iScience"},{"key":"2025081611100845000_2025.08.13.670146v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm185"},{"key":"2025081611100845000_2025.08.13.670146v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/13810"},{"key":"2025081611100845000_2025.08.13.670146v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2275"},{"key":"2025081611100845000_2025.08.13.670146v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/s004010050582"},{"key":"2025081611100845000_2025.08.13.670146v1.7","doi-asserted-by":"publisher","DOI":"10.1007\/s002210050463"},{"key":"2025081611100845000_2025.08.13.670146v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9861(20001225)428:4<616::AID-CNE3>3.0.CO;2-K"},{"key":"2025081611100845000_2025.08.13.670146v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01150-1"},{"key":"2025081611100845000_2025.08.13.670146v1.10","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.nbd.2017.10.006","article-title":"A lack of GluN2A-containing NMDA receptors confers a vulnerability to redox dysregulation: Consequences on parvalbumin interneurons, and their perineuronal nets","volume":"109","year":"2018","journal-title":"Neurobiol Dis"},{"key":"2025081611100845000_2025.08.13.670146v1.11","doi-asserted-by":"crossref","unstructured":"Carstens KE , Lustberg DJ , Shaughnessy EK , McCann KE , Alexander GM , Dudek SM (2021) Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome. J Clin Invest 131.","DOI":"10.1172\/JCI137221"},{"key":"2025081611100845000_2025.08.13.670146v1.12","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20822"},{"key":"2025081611100845000_2025.08.13.670146v1.13","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq145"},{"key":"2025081611100845000_2025.08.13.670146v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(98)01298-3"},{"key":"2025081611100845000_2025.08.13.670146v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.10.001"},{"key":"2025081611100845000_2025.08.13.670146v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/nature09582"},{"key":"2025081611100845000_2025.08.13.670146v1.17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.888612"},{"key":"2025081611100845000_2025.08.13.670146v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/nature10907"},{"key":"2025081611100845000_2025.08.13.670146v1.19","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3042-19.2020"},{"key":"2025081611100845000_2025.08.13.670146v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.12.004"},{"key":"2025081611100845000_2025.08.13.670146v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0393-5"},{"key":"2025081611100845000_2025.08.13.670146v1.22","doi-asserted-by":"crossref","unstructured":"Ehinger Y , Matagne V , Cunin V , Borloz E , Seve M , Bourgoin-Voillard S , Borges-Correia A , Villard L , Roux JC (2021) Analysis of Astroglial Secretomic Profile in the Mecp2-Deficient Male Mouse Model of Rett Syndrome. Int J Mol Sci 22.","DOI":"10.3390\/ijms22094316"},{"key":"2025081611100845000_2025.08.13.670146v1.23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.010830"},{"key":"2025081611100845000_2025.08.13.670146v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.07.030"},{"key":"2025081611100845000_2025.08.13.670146v1.25","doi-asserted-by":"publisher","DOI":"10.1093\/BIOINFORMATICS\/BTZ931"},{"key":"2025081611100845000_2025.08.13.670146v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2012.05.055"},{"key":"2025081611100845000_2025.08.13.670146v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/85899"},{"key":"2025081611100845000_2025.08.13.670146v1.28","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410140412"},{"key":"2025081611100845000_2025.08.13.670146v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02173-9"},{"key":"2025081611100845000_2025.08.13.670146v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6036"},{"key":"2025081611100845000_2025.08.13.670146v1.31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.18.5758"},{"key":"2025081611100845000_2025.08.13.670146v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10520"},{"key":"2025081611100845000_2025.08.13.670146v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14077"},{"key":"2025081611100845000_2025.08.13.670146v1.34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1506499112"},{"key":"2025081611100845000_2025.08.13.670146v1.35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2010.06878.x"},{"key":"2025081611100845000_2025.08.13.670146v1.36","doi-asserted-by":"crossref","unstructured":"Lau BYB , Layo DE , Emery B , Everett M , Kumar A , Stevenson P , Reynolds KG , Cherosky A , Bowyer SH , Roth S , Fisher DG , McCord RP , Krishnan K (2020) Lateralized Expression of Cortical Perineuronal Nets during Maternal Experience is Dependent on MECP2. eNeuro 7.","DOI":"10.1101\/787267"},{"key":"2025081611100845000_2025.08.13.670146v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3550"},{"key":"2025081611100845000_2025.08.13.670146v1.38","doi-asserted-by":"crossref","unstructured":"Lemieux SP , Lev-Ram V , Tsien RY , Ellisman MH (2023) Perineuronal nets and the neuronal extracellular matrix can be imaged by genetically encoded labeling of HAPLN1 in vitro and in vivo. bioRxiv.","DOI":"10.1101\/2023.11.29.569151"},{"key":"2025081611100845000_2025.08.13.670146v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/nature10214"},{"key":"2025081611100845000_2025.08.13.670146v1.40","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0324-09.2009"},{"key":"2025081611100845000_2025.08.13.670146v1.41","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-17-07536.2002"},{"key":"2025081611100845000_2025.08.13.670146v1.42","doi-asserted-by":"crossref","unstructured":"Moissidis M , Abbasova L , Selten M , Alis R , Bernard C , Dominguez-Canterla Y , Oozeer F , Qin S , Kelly A , Modol L , Vasistha NA , Jones B , Dhami P , Khodosevich K , Hamid F , Lavender P , Flames N , Marin O (2025) A postnatal molecular switch drives activity-dependent maturation of parvalbumin interneurons. Cell.","DOI":"10.1016\/j.cell.2025.06.029"},{"key":"2025081611100845000_2025.08.13.670146v1.43","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2014.0046"},{"key":"2025081611100845000_2025.08.13.670146v1.44","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2657-13.2013"},{"key":"2025081611100845000_2025.08.13.670146v1.45","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhz085"},{"key":"2025081611100845000_2025.08.13.670146v1.46","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0880-20.2020"},{"key":"2025081611100845000_2025.08.13.670146v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2019.04.004"},{"key":"2025081611100845000_2025.08.13.670146v1.48","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072699"},{"key":"2025081611100845000_2025.08.13.670146v1.49","doi-asserted-by":"crossref","unstructured":"Rakela B , Brehm P , Mandel G (2018) Astrocytic modulation of excitatory synaptic signaling in a mouse model of Rett syndrome. Elife 7.","DOI":"10.7554\/eLife.31629"},{"key":"2025081611100845000_2025.08.13.670146v1.50","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade6530"},{"key":"2025081611100845000_2025.08.13.670146v1.51","first-page":"723","article-title":"[On a unusual brain atrophy syndrome in hyperammonemia in childhood]","volume":"116","year":"1966","journal-title":"Wien Med Wochenschr"},{"key":"2025081611100845000_2025.08.13.670146v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2019.146644"},{"key":"2025081611100845000_2025.08.13.670146v1.53","doi-asserted-by":"crossref","first-page":"105636","DOI":"10.1016\/j.nbd.2022.105636","article-title":"Vitamin D modulates cortical transcriptome and behavioral phenotypes in an Mecp2 heterozygous Rett syndrome mouse model","volume":"165","year":"2022","journal-title":"Neurobiol Dis"},{"key":"2025081611100845000_2025.08.13.670146v1.54","doi-asserted-by":"crossref","unstructured":"Ribeiro MC , Moore SM , Kishi N , Macklis JD , MacDonald JL (2020) Vitamin D Supplementation Rescues Aberrant NF-kappaB Pathway Activation and Partially Ameliorates Rett Syndrome Phenotypes in Mecp2 Mutant Mice. eNeuro 7.","DOI":"10.1523\/ENEURO.0167-20.2020"},{"key":"2025081611100845000_2025.08.13.670146v1.55","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf5273"},{"key":"2025081611100845000_2025.08.13.670146v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2931"},{"key":"2025081611100845000_2025.08.13.670146v1.57","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"2025081611100845000_2025.08.13.670146v1.58","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6267-11.2013"},{"key":"2025081611100845000_2025.08.13.670146v1.59","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1122-18.2018"},{"key":"2025081611100845000_2025.08.13.670146v1.60","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0838-23.2023"},{"key":"2025081611100845000_2025.08.13.670146v1.61","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912257106"},{"key":"2025081611100845000_2025.08.13.670146v1.62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1817222116"},{"key":"2025081611100845000_2025.08.13.670146v1.63","doi-asserted-by":"crossref","first-page":"108504","DOI":"10.1016\/j.jbc.2025.108504","article-title":"Contactin-1 is a critical neuronal cell surface receptor for perineuronal net structure","volume":"301","year":"2025","journal-title":"J Biol Chem"},{"key":"2025081611100845000_2025.08.13.670146v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.104952"},{"key":"2025081611100845000_2025.08.13.670146v1.65","doi-asserted-by":"crossref","unstructured":"Sterin I , Niazi A , Kim J , Park J , Park S (2024) Novel extracellular matrix architecture on excitatory neurons revealed by HaloTag-HAPLN1. bioRxiv.","DOI":"10.1101\/2024.03.29.587384"},{"key":"2025081611100845000_2025.08.13.670146v1.66","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2674-14.2014"},{"key":"2025081611100845000_2025.08.13.670146v1.67","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.25"},{"key":"2025081611100845000_2025.08.13.670146v1.68","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-452-0_5"},{"key":"2025081611100845000_2025.08.13.670146v1.69","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-012-1375-y"},{"key":"2025081611100845000_2025.08.13.670146v1.70","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0057-11.2011"},{"key":"2025081611100845000_2025.08.13.670146v1.71","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu008"},{"key":"2025081611100845000_2025.08.13.670146v1.72","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2012.09.005"},{"key":"2025081611100845000_2025.08.13.670146v1.73","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2014.11.013"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.08.13.670146","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:20:36Z","timestamp":1768468836000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.08.13.670146"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,13]]},"references-count":73,"URL":"https:\/\/doi.org\/10.1101\/2025.08.13.670146","relation":{},"subject":[],"published":{"date-parts":[[2025,8,13]]},"subtype":"preprint"}}