{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:18:17Z","timestamp":1790914697770,"version":"4.1.0"},"reference-count":36,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":868,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_U142684173"],"award-info":[{"award-number":["MC_U142684173"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["UM1HG006348"],"award-info":[{"award-number":["UM1HG006348"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Loss of function mutations in the human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and ex vivo studies have implicated FRRS1L in AMPA receptor biogenesis, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse Frrs1l null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking Frrs1l suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, Frrs1l\u2212\/\u2212 mice were hyperactive irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic recordings also revealed abnormal EEG in Frrs1l\u2212\/\u2212 mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of Frrs1l\u2212\/\u2212 mice, while the general levels of several other synaptic components remained unchanged with no obvious alterations in the number of synapses. Furthermore, we established that Frrsl1 deletion results in an increased proportion of immature AMPA receptors, indicated by incomplete glycosylation of GLUA2 and GLUA4 AMPA receptor proteins. This incomplete maturation leads to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time in vivo, how loss of FRRS1L function can affect glutamatergic signalling and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.<\/jats:p>","DOI":"10.1242\/dmm.036806","type":"journal-article","created":{"date-parts":[[2019,1,28]],"date-time":"2019-01-28T09:01:19Z","timestamp":1548666079000},"source":"Crossref","is-referenced-by-count":28,"title":["Loss of\n                    <i>Frrs1l<\/i>\n                    disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities"],"prefix":"10.1242","author":[{"given":"Michelle","family":"Stewart","sequence":"first","affiliation":[{"name":"MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petrina","family":"Lau","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth","family":"Banks","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasneer Sonia","family":"Bains","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Castroflorio","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L.","family":"Oliver","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine L.","family":"Dixon","sequence":"additional","affiliation":[{"name":"University College London (UCL) London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Kruer","sequence":"additional","affiliation":[{"name":"Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitri M.","family":"Kullmann","sequence":"additional","affiliation":[{"name":"University College London (UCL) London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abraham","family":"Acevedo-Arozena","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario de Canarias, Fundaci\u00f3n Canaria de Investigaci\u00f3n Sanitaria and Instituto de Tecnolog\u00edas Biom\u00e9dicas (ITB), Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Wells","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0958-0083","authenticated-orcid":false,"given":"Silvia","family":"Corrochano","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5550-0334","authenticated-orcid":false,"given":"Patrick M.","family":"Nolan","sequence":"additional","affiliation":[{"name":"MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2019,1,1]]},"reference":[{"key":"2021042513034134200_DMM036806C1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fnbeh.2016.00106","article-title":"Analysis of individual mouse activity in group housed animals of different inbred strains using a novel automated home cage analysis system","volume":"10","author":"Bains","year":"2016","journal-title":"Front. 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