{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T03:31:36Z","timestamp":1793244696927,"version":"4.5.0"},"reference-count":55,"publisher":"Society for Neuroscience","issue":"30","license":[{"start":{"date-parts":[[2027,1,29]],"date-time":"2027-01-29T00:00:00Z","timestamp":1801180800000},"content-version":"vor","delay-in-days":226,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"name":"AMED-CREST"},{"name":"JSPS KAKENHI"},{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["jneurosci.org"],"crossmark-restriction":true},"short-container-title":["J. Neurosci."],"accepted":{"date-parts":[[2026,5,28]]},"published-print":{"date-parts":[[2026,7,29]]},"abstract":"<jats:p>\n                    SLC6A8 encodes the creatine transporter (CRT), which mediates creatine transport across the plasma membrane in the brain, including the bloodbrain barrier and neurons. Creatine transporter deficiency (CTD), caused by pathogenic variants in\n                    <jats:italic>SLC6A8<\/jats:italic>\n                    , leads to cerebral creatine depletion and cognitive impairment. Here, we investigated the developmental molecular mechanisms underlying CTD using the pathogenic c.1681G&gt;C (G561R) variant of\n                    <jats:italic>Slc6a8<\/jats:italic>\n                    , which corresponds to a variant identified in\n                    <jats:italic>SLC6A8<\/jats:italic>\n                    in a patient with CTD. In vitro analyses using HEK293 cells expressing mutant mouse CRT carrying the G561R variant demonstrated impaired N-glycan maturation and plasma membrane localization of the transporter, resulting in markedly reduced creatine uptake, consistent with previous reports on the corresponding human CRT variant. To investigate the in vivo effects of this pathogenic variant, we generated CRT-G561R knock-in mice by introducing the c.1681G&gt;C point mutation into the mouse\n                    <jats:italic>Slc6a8<\/jats:italic>\n                    gene using the CRISPR\/Cas9 system. These male mice exhibited severe reductions in brain creatine levels, postnatal growth retardation, and impaired spatial memory, despite preserved gross brain morphology. Quantitative proteomic analyses of the hippocampus and cerebral cortex during postnatal development revealed region-dependent protein alterations in CTD. The hippocampus showed pronounced early postnatal remodeling involving proteins related to actin cytoskeleton organization and vesicle-mediated membrane trafficking, whereas the cerebral cortex exhibited a more gradual response involving creatine biosynthesis-related enzymes and later-emerging mitochondrial pathways, including the mitochondrial translation machinery. These findings demonstrate stage- and region-dependent proteomic remodeling during postnatal brain development in CTD.\n                  <\/jats:p>","DOI":"10.1523\/jneurosci.2010-25.2026","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T17:55:17Z","timestamp":1781718917000},"page":"e2010252026","update-policy":"https:\/\/doi.org\/10.1523\/jneurosci.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Stage- and Region-Dependent Proteomic Alterations in a Mouse Model of Creatine Transporter Deficiency"],"prefix":"10.1523","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8862-471X","authenticated-orcid":false,"given":"Shingo","family":"Ito","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumi","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuki","family":"Uemura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5888-5054","authenticated-orcid":false,"given":"Michihiko","family":"Sugimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Kumabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayaka","family":"Miyano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruya","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Tashiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumu","family":"Ieiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moeka","family":"Umezaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoma","family":"Chikamatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Masuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satohiro","family":"Nakao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Nakagata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Takeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimi","family":"Araki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumio","family":"Ohtsuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"2026102703501005000_46.30.e2010252026.1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1007\/s12031-019-01405-w","article-title":"Deletion of the creatine transporter (Slc6a8) in dopaminergic neurons leads to hyperactivity in mice","volume":"70","author":"Abdulla","year":"2020","journal-title":"J Mol Neurosci"},{"key":"2026102703501005000_46.30.e2010252026.2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw252"},{"key":"2026102703501005000_46.30.e2010252026.3","doi-asserted-by":"crossref","first-page":"2633105520935104","DOI":"10.1177\/2633105520935104","article-title":"The effects of early-life iron deficiency on brain energy metabolism","volume":"15","author":"Bastian","year":"2020","journal-title":"Neurosci Insights"},{"key":"2026102703501005000_46.30.e2010252026.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2010.06935.x"},{"key":"2026102703501005000_46.30.e2010252026.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.08.016"},{"key":"2026102703501005000_46.30.e2010252026.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2011.12.022"},{"key":"2026102703501005000_46.30.e2010252026.7","doi-asserted-by":"crossref","first-page":"e89317","DOI":"10.7554\/eLife.89317","article-title":"Suggestion of creatine as a new neurotransmitter by approaches ranging from chemical analysis and biochemistry to electrophysiology","volume":"12","author":"Bian","year":"2023","journal-title":"Elife"},{"key":"2026102703501005000_46.30.e2010252026.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.07.006"},{"key":"2026102703501005000_46.30.e2010252026.9","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-011-9433-2"},{"key":"2026102703501005000_46.30.e2010252026.10","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1941-16.2016"},{"key":"2026102703501005000_46.30.e2010252026.11","doi-asserted-by":"crossref","first-page":"e140173","DOI":"10.1172\/jci.insight.140173","article-title":"Creatine transporter deficiency impairs stress adaptation and brain energetics homeostasis","volume":"6","author":"Chen","year":"2021","journal-title":"JCI Insight"},{"key":"2026102703501005000_46.30.e2010252026.12","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M113.031591"},{"key":"2026102703501005000_46.30.e2010252026.13","doi-asserted-by":"publisher","DOI":"10.1023\/A:1022487218904"},{"key":"2026102703501005000_46.30.e2010252026.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0638-x"},{"key":"2026102703501005000_46.30.e2010252026.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-80824-x"},{"key":"2026102703501005000_46.30.e2010252026.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2021.12.005"},{"key":"2026102703501005000_46.30.e2010252026.17","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4115-14.2015"},{"key":"2026102703501005000_46.30.e2010252026.18","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2018.1"},{"key":"2026102703501005000_46.30.e2010252026.19","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0223"},{"key":"2026102703501005000_46.30.e2010252026.20","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3311"},{"key":"2026102703501005000_46.30.e2010252026.21","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201003008"},{"key":"2026102703501005000_46.30.e2010252026.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.01.010"},{"key":"2026102703501005000_46.30.e2010252026.23","doi-asserted-by":"crossref","first-page":"26738","DOI":"10.1038\/s41598-025-11386-z","article-title":"Effects of SLC6A8 mutation-induced creatine deficiency on cellular function in fibroblasts","volume":"15","author":"Ito","year":"2025","journal-title":"Sci Rep"},{"key":"2026102703501005000_46.30.e2010252026.24","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.braindev.2013.08.004","article-title":"Urine screening for patients with developmental disabilities detected a patient with creatine transporter deficiency due to a novel missense mutation in SLC6A8","volume":"36","author":"Kato","year":"2014","journal-title":"Brain Dev"},{"key":"2026102703501005000_46.30.e2010252026.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.02.032"},{"key":"2026102703501005000_46.30.e2010252026.26","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59373"},{"key":"2026102703501005000_46.30.e2010252026.27","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-6336-3"},{"key":"2026102703501005000_46.30.e2010252026.28","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1021\/acs.molpharmaceut.9b00114","article-title":"Large-scale quantitative comparison of plasma transmembrane proteins between two human blood-brain barrier model cell lines, hCMEC\/D3 and HBMEC\/ci","volume":"16","author":"Masuda","year":"2019","journal-title":"Mol Pharm"},{"key":"2026102703501005000_46.30.e2010252026.29","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2018.16"},{"key":"2026102703501005000_46.30.e2010252026.30","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41598-018-37303-1","article-title":"A nervous system-specific model of creatine transporter deficiency recapitulates the cognitive endophenotype of the disease: a longitudinal study","volume":"9","author":"Molinaro","year":"2019","journal-title":"Sci Rep"},{"key":"2026102703501005000_46.30.e2010252026.31","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1177\/0271678X20941449","article-title":"Efficient isolation of brain capillary from a single frozen mouse brain for protein expression analysis","volume":"41","author":"Ogata","year":"2021","journal-title":"J Cereb Blood Flow Metab"},{"key":"2026102703501005000_46.30.e2010252026.32","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-200211000-00006"},{"key":"2026102703501005000_46.30.e2010252026.33","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.23"},{"key":"2026102703501005000_46.30.e2010252026.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2024.106550"},{"key":"2026102703501005000_46.30.e2010252026.35","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2120-21.2022"},{"key":"2026102703501005000_46.30.e2010252026.36","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1021\/acs.biochem.9b00956","article-title":"Classification of the molecular defects associated with pathogenic variants of the SLC6A8 creatine transporter","volume":"59","author":"Salazar","year":"2020","journal-title":"Biochemistry"},{"key":"2026102703501005000_46.30.e2010252026.37","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.3390\/biomedicines9091092","article-title":"Early life stress and metabolic plasticity of brain cells: impact on neurogenesis and angiogenesis","volume":"9","author":"Salmina","year":"2021","journal-title":"Biomedicines"},{"key":"2026102703501005000_46.30.e2010252026.38","doi-asserted-by":"publisher","DOI":"10.1023\/A:1022443503883"},{"key":"2026102703501005000_46.30.e2010252026.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2005.08.004"},{"key":"2026102703501005000_46.30.e2010252026.40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016187"},{"key":"2026102703501005000_46.30.e2010252026.41","doi-asserted-by":"publisher","DOI":"10.1159\/000508054"},{"key":"2026102703501005000_46.30.e2010252026.42","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20050857"},{"key":"2026102703501005000_46.30.e2010252026.43","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-008-0051-8"},{"key":"2026102703501005000_46.30.e2010252026.44","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1113"},{"key":"2026102703501005000_46.30.e2010252026.45","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-017-2446-y"},{"key":"2026102703501005000_46.30.e2010252026.46","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12461"},{"key":"2026102703501005000_46.30.e2010252026.47","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12137"},{"key":"2026102703501005000_46.30.e2010252026.48","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1248\/bpb.b16-00582","article-title":"Abnormal N-glycosylation of a novel missense creatine transporter mutant, G561R, associated with cerebral creatine deficiency syndromes alters transporter activity and localization","volume":"40","author":"Uemura","year":"2017","journal-title":"Biol Pharm Bull"},{"key":"2026102703501005000_46.30.e2010252026.49","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-020-2779-0"},{"key":"2026102703501005000_46.30.e2010252026.50","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-011-9345-1"},{"key":"2026102703501005000_46.30.e2010252026.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2018.07.041"},{"key":"2026102703501005000_46.30.e2010252026.52","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-011-0877-3"},{"key":"2026102703501005000_46.30.e2010252026.53","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.3.1107"},{"key":"2026102703501005000_46.30.e2010252026.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.ghir.2015.09.004"},{"key":"2026102703501005000_46.30.e2010252026.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09234-6"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.2010-25.2026","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.2010-25.2026","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T02:38:56Z","timestamp":1793241536000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.2010-25.2026"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":55,"journal-issue":{"issue":"30","published-online":{"date-parts":[[2026,7,29]]},"published-print":{"date-parts":[[2026,7,29]]}},"alternative-id":["10.1523\/JNEUROSCI.2010-25.2026"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.2010-25.2026","relation":{},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]}}}