{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:03:51Z","timestamp":1768511031400,"version":"3.49.0"},"posted":{"date-parts":[[2024,3,29]]},"group-title":"Animal Behavior and Cognition","reference-count":96,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,3,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Nonketotic hyperglycinemia due to deficient glycine cleavage enzyme activity causes a severe neonatal epileptic encephalopathy. Current therapies based on mitigating glycine excess have only limited impact. An animal model with postnatal phenotyping is needed to explore new therapeutic approaches. We developed a\n                  <jats:italic>Gldc<\/jats:italic>\n                  p.Ala394Val mutant model and bred it to congenic status in 2 colonies on C57Bl\/6J (B6) and J129X1\/SvJ (J129) backgrounds. Mutant mice had reduced P-protein and enzyme activity indicating a hypomorphic mutant. Glycine levels were increased in blood and brain regions, exacerbated by dietary glycine, with higher levels in female than male J129 mice. Birth defects were more prevalent in mutant B6 than J129 mice, and hydrocephalus was more frequent in B6 (40%) compared to J129 (none). The hydrocephalus rate was increased by postnatal glycine challenge in B6 mice, more so when delivered from the first neonatal week than from the fourth. Mutant mice had reduced weight gain following weaning until the eighth postnatal week, which was exacerbated by glycine loading. The electrographic spike rate was increased in mutant mice following glycine loading, but no seizures were observed. The alpha\/delta band intensity ratio was decreased in the left cortex in female J129 mice, which were less active in an open field test and explored less in a Y-maze, suggesting an encephalopathic effect. Mutant mice showed no evidence of memory dysfunction. This partial recapitulation of human symptoms and biochemistry will facilitate the evaluation of new therapeutic approaches with an early postnatal time window likely most effective.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Take home message<\/jats:title>\n                  <jats:p>A mouse model of nonketotic hyperglycinemia is described that shows postnatal abnormalities in glycine levels, neural tube defects, body weight, electroencephalographic recordings, and in activity in young mice making it amenable for the evaluation of novel treatment interventions.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Author contributions<\/jats:title>\n                  <jats:p>Study concept and design: JVH, MHM, NB, KNM<\/jats:p>\n                  <jats:p>Animal study data: MAS, HJ, NB, MHM, JC, CB<\/jats:p>\n                  <jats:p>Biochemical and genetic studies: MAS, RAVH, MWF<\/jats:p>\n                  <jats:p>Statistical analysis: NB, JVH<\/jats:p>\n                  <jats:p>First draft writing: JVH, NB, MHM<\/jats:p>\n                  <jats:p>Critical rewriting: MAS, NB, MHM, TAB, JC, MWF, KNM, JVH<\/jats:p>\n                  <jats:p>Final responsibility, guarantor, and communicating author: JVH<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Competing interest statement<\/jats:title>\n                  <jats:p>The University of Colorado (JVH, MS, KNM, HJ) has the intention to file Intellectual property protection for certain biochemical treatments of NKH. Otherwise, the authors have stated that they had no interests that might be perceived as posing a conflict or bias to this subject matter.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding support<\/jats:title>\n                  <jats:p>Financial support is acknowledged form the NKH Crusaders, Brodyn\u2019s Friends, Nora Jane Almany Foundation, the Dickens Family Foundation, the Lucas John Foundation, Les Petits Bourdons, Joseph\u2019s Fund, the Barnett Family, Maud &amp; Vic Foundation, Lucy\u2019s BEElievers fund, Hope for NKH, Madi\u2019s Mission NKH fund, and from Dr. and Ms. Shaw, and the University of Colorado Foundation NKH research fund. The study was supported by a grant (CNS-X-19-103) from the University of Colorado School of Medicine and the Colorado Clinical Translational Science Institute, which is supported by NIH\/NCATS Colorado CTSA Grant Number UL1 TR002535. Contents are the authors\u2019 sole responsibility and do not necessarily represent official NIH views. All funding sources had no role in the design or execution of the study, the interpretation of data, or the writing of the study.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Ethics approval on Laboratory Animal Studies<\/jats:title>\n                  <jats:p>Mouse studies were carried out with approval from the Institutional Animal Care and Use Committee of the University of Colorado Anschutz Medical Campus (IACUC# 00413).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Data sharing statement<\/jats:title>\n                  <jats:p>The data that support the findings of this study are available from the corresponding author upon reasonable request.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.03.26.586818","type":"posted-content","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T17:45:17Z","timestamp":1711734317000},"source":"Crossref","is-referenced-by-count":0,"title":["Deep postnatal phenotyping of a new mouse model of nonketotic hyperglycinemia"],"prefix":"10.64898","author":[{"given":"Michael A.","family":"Swanson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Busquet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Carlsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Connie","family":"Brindley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim A.","family":"Benke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roxanne A.","family":"Van Hove","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marisa W.","family":"Friederich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth N.","family":"MacLean","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael H.","family":"Mesches","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johan L.K.","family":"Van Hove","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024040214350889000_2024.03.26.586818v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.74"},{"key":"2024040214350889000_2024.03.26.586818v1.2","unstructured":"Van Hove J , Coughlin CI , Swanson M , Hennermann J. 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