<?xml version="1.0" encoding="utf-8" standalone="yes"?>
<TEI xmlns="http://www.tei-c.org/ns/1.0">
  <teiHeader>
    <fileDesc>
      <titleStmt>
        <title type="main">New insights into creatine transporter deficiency</title>
        <title type="sub">Identification of neuropathological and metabolic targets for treatment</title>
        <author>
          <persName n="1" ref="https://orcid.org/0000-0003-1690-5448" type="ORCID">
            <forename>Angelo</forename>
            <surname>Molinaro</surname>
          </persName>
        </author>
      </titleStmt>
      <publicationStmt>
        <publisher>Firenze University Press</publisher>
        <pubPlace>Florence</pubPlace>
        <date when="2020">2020</date>
        <idno type="DOI">https://doi.org/10.36253/978-88-5518-082-5</idno>
        <availability>
          <p>Available for academic research purposes</p>
          <p>Open Access</p>
          <p>Copyright Author(s)</p>
          <licence source="text" target="https://creativecommons.org/licenses/by/4.0/legalcode">
            <p>Content licence CC BY 4.0</p>
          </licence>
          <licence source="metadata" target="https://creativecommons.org/publicdomain/zero/1.0/legalcode">
            <p>Metadata licence CC0 1.0</p>
          </licence>
        </availability>
      </publicationStmt>
      <seriesStmt>
        <title>Premio Tesi di Dottorato</title>
        <idno type="ISSN" subtype="print">2612-8039</idno>
        <idno type="ISSN" subtype="electronic">2612-8020</idno>
      </seriesStmt>
      <sourceDesc>
        <bibl type="monograph">
          <edition n="1">Digital edition PDF</edition>
          <date>2020</date>
          <idno type="ISBN" subtype="electronic">978-88-5518-082-5</idno>
          <biblScope unit="page">116 pages</biblScope>
          <extent>0,00 MB</extent>
          <availability status="free">
            <p>This is original content, published in Open Access. It is also available to read for free online at <ref target="https://media.fupress.com/files/pdf/24/4380/14404">https://media.fupress.com/files/pdf/24/4380/14404</ref></p>
          </availability>
        </bibl>
        <bibl type="monograph">
          <edition n="2">Digital edition XML</edition>
          <date>2020</date>
          <idno type="ISBN" subtype="electronic">978-88-5518-083-2</idno>
          <availability status="free">
            <p>It is available to read for free online</p>
          </availability>
        </bibl>
        <bibl type="monograph">
          <edition n="3">Print edition</edition>
          <date>2020</date>
          <idno type="ISBN" subtype="print">978-88-5518-081-8</idno>
          <biblScope unit="page">116 pages</biblScope>
          <availability status="restricted">
            <p>It is available for online purchase at <ref target="https://books.fupress.com/isbn/9788855180825">https://books.fupress.com/isbn/9788855180825</ref></p>
          </availability>
        </bibl>
      </sourceDesc>
    </fileDesc>
    <encodingDesc>
      <appInfo>
        <application version="2.2" ident="Booksflow">
          <desc>Digital edition XML powered by Booksflow</desc>
        </application>
      </appInfo>
    </encodingDesc>
    <profileDesc>
      <creation>
        <tag>peer-reviewed</tag>
        <rs type="FUP_policy" source="https://doi.org/10.36253/fup_best_practice">Firenze University Press Best Practice in Scholarly Publishing</rs>
        <rs type="scientific_cloud" source="https://doi.org/10.36253/fup_best_practice.2">FUP Scientific Cloud for Books</rs>
        <rs type="peer_review" resp="scientific_board" source="https://books.fupress.com/scientific-board/c/104">Premio Tesi di Dottorato 2019</rs>
      </creation>
      <abstract xml:lang="it">
        <p>Creatine (Cr) transporter deficiency (CCDS1) is a very rare and severe condition due to impaired energetic metabolism. In this work we showed for the first time the following facts: this diseases is a progressive neurodegenerative disorder in which a set of maladaptive compensatory mechanisms leads to a progressive damage of brain functions; cell energy metabolism and mitochondria seem strongly involved in the pathogenesis and they could represent useful potential targets for therapeutic interventions; inflammation seems to play an important part in this progressive damage, and this observation can pave the way to treatment strategies; neural circuits disruption involving inhibitory systems could give a huge contribute to many of the clinical aspects observed in patients, as epilepsy and cognitive impairment, since the excitatory/inhibitory balance is fundamental for the normal function of neural circuits. Factors outside the CNS are important in the pathogenesis of at least some aspects of the disorder, since the conditional KO model show difference in the timing of onset of some cognitive defects and in the presence of stereotypies.</p>
      </abstract>
      <textClass>
        <keywords>
          <list>
            <item>creatine</item>
            <item>transporter</item>
            <item>brain</item>
          </list>
        </keywords>
      </textClass>
    </profileDesc>
  </teiHeader>
  <text>
    <body>
      <p>It is available online at https://doi.org/10.36253/978-88-5518-082-5<ref target="https://doi.org/10.36253/978-88-5518-082-5" /></p>
      <div>
        <listBibl>
          <head>References</head>
          <bibl n="7665">
            <bibl>Ahmed, Z., Sheng, H., Xu, Y., Lin, W.-L., Innes, A. E., Gass, J., Yu, X., Hou, H., Chiba, S., Yamanouchi, K., Leissring, M., Petrucelli, L., Nishihara, M., Hutton, M. L., McGowan, E., Dickson, D. W., Lewis, J. and Lewis, J. (2010) ‘Accelerated Lipofuscinosis and Ubiquitination in Granulin Knockout Mice Suggest a Role for Progranulin in Successful Aging’, The American Journal of Pathology, 177(1), pp. 311–324. .</bibl>
            <idno type="DOI">10.2353/ajpath.2010.090915</idno>
          </bibl>
          <bibl n="7666">
            <bibl>Alcaide, P., Merinero, B., Ruiz-Sala, P., Richard, E., Navarrete, R., Arias, &amp;#193;., Ribes, A., Artuch, R., Campistol, J., Ugarte, M. and Rodr&amp;#237;guez-Pombo, P. (2011) ‘Defining the pathogenicity of creatine deficiency syndrome’, Human Mutation. Wiley-Blackwell, 32(3), pp. 282–291.</bibl>
            <idno type="DOI">10.1002/humu.21421</idno>
          </bibl>
          <bibl n="7667">
            <bibl>Alessandr&amp;#236;, M. G., Celati, L., Battini, R., Casarano, M. and Cioni, G. (2005) ‘Gas chromatography/mass spectrometry assay for arginine: Glycine-amidinotransferase deWciency’, ANALYTICAL BIOCHEMISTRY, 343, pp. 356–358.</bibl>
            <idno type="DOI">10.1016/j.ab.2005.05.003</idno>
          </bibl>
          <bibl n="7668">
            <bibl>Almeida, L. S., Salomons, G. S., Hogenboom, F., Jakobs, C. and Schoffelmeer, A. N. M. (2006) ‘Exocytotic release of creatine in rat brain.’, Synapse (New York, N.Y.), 60(2), pp. 118–23.</bibl>
            <idno type="DOI">10.1002/syn.20280</idno>
          </bibl>
          <bibl n="7669">
            <bibl>Andres, R. H., Ducray, A. D., Schlattner, U., Wallimann, T. and Widmer, H. R. (2008) ‘Functions and effects of creatine in the central nervous system.’, Brain research bulletin, 76(4), pp. 329–43.</bibl>
            <idno type="DOI">10.1016/j.brainresbull.2008.02.035</idno>
          </bibl>
          <bibl n="7670">
            <bibl>Anselm, I. M., Alkuraya, F. S., Salomons, G. S., Jakobs, C., Fulton, A. B., Mazumdar, M., Rivkin, M., Frye, R., Poussaint, T. Y., Marsden, D. and Marsden, D. (2006) ‘X-linked creatine transporter defect: A report on two unrelated boys with a severe clinical phenotype’, Journal of Inherited Metabolic Disease, 29(1), pp. 214–219.</bibl>
            <idno type="DOI">10.1007/s10545-006-0123-4</idno>
          </bibl>
          <bibl n="7671">
            <bibl>Assun&amp;#231;&amp;#227;o, M., Santos-Marques, M. J., Carvalho, F., Lukoyanov, N. V. and Andrade, J. P. (2011) ‘Chronic green tea consumption prevents age-related changes in rat hippocampal formation’, Neurobiology of Aging, 32(4), pp. 707–717.</bibl>
            <idno type="DOI">10.1016/j.neurobiolaging.2009.03.016</idno>
          </bibl>
          <bibl n="7672">
            <bibl>Balsom, P. D., S&amp;#246;derlund, K. and Ekblom, B. (1994) ‘Creatine in humans with special reference to creatine supplementation.’, Sports medicine (Auckland, N.Z.), 18(4), pp. 268–80.</bibl>
            <idno type="DOI">10.2165/00007256-199418040-00005</idno>
          </bibl>
          <bibl n="7673">
            <bibl>Bamburg, J. R. and Bernstein, B. W. (2016) ‘Actin dynamics and cofilin-actin rods in alzheimer disease’, Cytoskeleton, 73(9), pp. 477–497.</bibl>
            <idno type="DOI">10.1002/cm.21282</idno>
          </bibl>
          <bibl n="7674">
            <bibl>Bano, D., Agostini, M., Melino, G. and Nicotera, P. (2011) ‘Ageing, Neuronal Connectivity and Brain Disorders: An Unsolved Ripple Effect’, Molecular Neurobiology, 43(2), pp. 124–130.</bibl>
            <idno type="DOI">10.1007/s12035-011-8164-6</idno>
          </bibl>
          <bibl n="7675">
            <bibl>Baroncelli, L., Alessandr&amp;#236;, M. G., Tola, J., Putignano, E., Migliore, M., Amendola, E., Gross, C., Leuzzi, V., Cioni, G. and Pizzorusso, T. (2014) ‘A novel mouse model of creatine transporter deficiency.’, F1000Research, 3(0), p. 228.</bibl>
            <idno type="DOI">10.12688/f1000research.5369.1</idno>
          </bibl>
          <bibl n="7676">
            <bibl>Bartsch, T. and Wulff, P. (2015) ‘The hippocampus in aging and disease: From plasticity to vulnerability’, Neuroscience, 309, pp. 1–16.</bibl>
            <idno type="DOI">10.1016/j.neuroscience.2015.07.084</idno>
          </bibl>
          <bibl n="7677">
            <bibl>Beck, H., Flynn, K., Lindenberg, K. S., Schwarz, H., Bradke, F., Di Giovanni, S. and Knoll, B. (2012) ‘Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics’, Proceedings of the National Academy of Sciences, 109(38), pp. E2523–E2532.</bibl>
            <idno type="DOI">10.1073/pnas.1208141109</idno>
          </bibl>
          <bibl n="7678">
            <bibl>Bender, A., Beckers, J., Schneider, I., H&amp;#246;lter, S. M., Haack, T., Ruthsatz, T., Vogt-Weisenhorn, D. M., Becker, L., Genius, J., Rujescu, D., Irmler, M., Mijalski, T., Mader, M., Quintanilla-Martinez, L., Fuchs, H., Gailus-Durner, V., de Angelis, M. H., Wurst, W., Schmidt, J. and Klopstock, T. (2008) ‘Creatine improves health and survival of mice’, Neurobiology of Aging, 29(9), pp. 1404–1411.</bibl>
            <idno type="DOI">10.1016/j.neurobiolaging.2007.03.001</idno>
          </bibl>
          <bibl n="7679">
            <bibl>Betsalel, O. T., Pop, A., Rosenberg, E. H., Fernandez-Ojeda, M., Creatine Transporter Research, Group, C., Jakobs, C. and Salomons, G. S. (2012) ‘Detection of variants in SLC6A8 and functional analysis of unclassified missense variants.’, Molecular genetics and metabolism, 105(4), pp. 596–601.</bibl>
            <idno type="DOI">10.1016/j.ymgme.2011.12.022</idno>
          </bibl>
          <bibl n="7680">
            <bibl>Bizzi, A., Bugiani, M., Salomons, G. S., Hunneman, D. H., Moroni, I., Estienne, M., Danesi, U., Jakobs, C. and Uziel, G. (2002) ‘X-linked creatine deficiency syndrome: A novel mutation in creatine transporter geneSLC6A8’, Annals of Neurology, 52(2), pp. 227–231.</bibl>
            <idno type="DOI">10.1002/ana.10246</idno>
          </bibl>
          <bibl n="7681">
            <bibl>Bories, C., Husson, Z., Guitton, M. J. and De Koninck, Y. (2013) ‘Differential balance of prefrontal synaptic activity in successful versus unsuccessful cognitive aging.’, The Journal of neuroscience : the official journal of the Society for Neuroscience, 33(4), pp. 1344–56.</bibl>
            <idno type="DOI">10.1523/JNEUROSCI.3258-12.2013</idno>
          </bibl>
          <bibl n="7682">
            <bibl>Braissant, O., Cagnon, L., Monnet-Tschudi, F., Speer, O., Wallimann, T., Honegger, P. and Henry, H. (2008) ‘Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency’, European Journal of Neuroscience, 27(7), pp. 1673–1685.</bibl>
            <idno type="DOI">10.1111/j.1460-9568.2008.06126.x</idno>
          </bibl>
          <bibl n="7683">
            <bibl>Braissant, O., Henry, H., Loup, M., Eilers, B. and Bachmann, C. (2001) ‘Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study.’, Brain research. Molecular brain research, 86(1–2), pp. 193–201.</bibl>
            <idno type="DOI">10.1016/s0169-328x(00)00269-2</idno>
          </bibl>
          <bibl n="7684">
            <bibl>Braissant, O., Henry, H., Villard, A.-M., Speer, O., Wallimann, T. and Bachmann, C. (2005) ‘Creatine synthesis and transport during rat embryogenesis: spatiotemporal expression of AGAT, GAMT and CT1.’, BMC Developmental Biology, 5(1), p. 9.</bibl>
            <idno type="DOI">10.1186/1471-213X-5-9</idno>
          </bibl>
          <bibl n="7685">
            <bibl>Brandenstein, L., Schweizer, M., Sedlacik, J., Fiehler, J. and Storch, S. (2016) ‘Lysosomal dysfunction and impaired autophagy in a novel mouse model deficient for the lysosomal membrane protein Cln7’, Human Molecular Genetics, 25(4), pp. 777–791.</bibl>
            <idno type="DOI">10.1093/hmg/ddv615</idno>
          </bibl>
          <bibl n="7686">
            <bibl>Brosnan, J. T. and Brosnan, M. E. (2007) ‘Creatine: Endogenous Metabolite, Dietary, and Therapeutic Supplement’, Annual Review of Nutrition, 27(1), pp. 241–261.</bibl>
            <idno type="DOI">10.1146/annurev.nutr.27.061406.093621</idno>
          </bibl>
          <bibl n="7687">
            <bibl>Brynczka, C. and Merrick, B. A. (2008) ‘The p53 transcriptional target gene wnt7b contributes to NGF-inducible neurite outgrowth in neuronal PC12 cells’, Differentiation, 76(7), pp. 795–808.</bibl>
            <idno type="DOI">10.1111/j.1432-0436.2007.00261.x</idno>
          </bibl>
          <bibl n="7688">
            <bibl>Carducci, C., Carducci, C., Santagata, S., Adriano, E., Artiola, C., Thellung, S., Gatta, E., Robello, M., Florio, T., Antonozzi, I., Leuzzi, V. and Balestrino, M. (2012) ‘In vitro study of uptake and synthesis of creatine and its precursors by cerebellar granule cells and astrocytes suggests some hypotheses on the physiopathology of the inherited disorders of creatine metabolism.’, BMC neuroscience. BioMed Central, 13, p. 41.</bibl>
            <idno type="DOI">10.1186/1471-2202-13-41</idno>
          </bibl>
          <bibl n="7689">Chanutin, A. (1926) ‘Tha fate of creatine when administered to man’, The Journal of biological chemistry, (2).</bibl>
          <bibl n="7690">
            <bibl>Chen, B. and Wang, Y. (2015) ‘Cofilin rod formation in neurons impairs neuronal structure and function.’, CNS &amp;amp; neurological disorders drug targets, 14(4), pp. 554–60.</bibl>
            <idno type="DOI">10.2174/1871527314666150225144052</idno>
          </bibl>
          <bibl n="7691">
            <bibl>Chilosi, A., Casarano, M., Comparini, A., Battaglia, F., Mancardi, M., Schiaffino, C., Tosetti, M., Leuzzi, V., Battini, R. and Cioni, G. (2012) ‘Neuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency’, Orphanet Journal of Rare Diseases, 7(1), p. 43.</bibl>
            <idno type="DOI">10.1186/1750-1172-7-43</idno>
          </bibl>
          <bibl n="7692">
            <bibl>Chilosi, A., Leuzzi, V., Battini, R., Tosetti, M., Ferretti, G., Comparini, A., Casarano, M., Moretti, E., Alessandri, M. G., Bianchi, M. C. and Cioni, G. (2008) ‘Treatment with L-arginine improves neuropsychological disorders in a child with creatine transporter defect.’, Neurocase, 14(2), pp. 151–61.</bibl>
            <idno type="DOI">10.1080/13554790802060821</idno>
          </bibl>
          <bibl n="7693">
            <bibl>Choe, C., Nabuurs, C., Stockebrand, M. C., Neu, A., Nunes, P., Morellini, F., Sauter, K., Schillemeit, S., Hermans-Borgmeyer, I., Marescau, B., Heerschap, A. and Isbrandt, D. (2013) ‘l-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome’, Human Molecular Genetics. Oxford University Press, 22(1), pp. 110–123.</bibl>
            <idno type="DOI">10.1093/hmg/dds407</idno>
          </bibl>
          <bibl n="7694">
            <bibl>Christian, K. M., Song, H. and Ming, G. (2014) ‘Functions and Dysfunctions of Adult Hippocampal Neurogenesis’, Annual Review of Neuroscience, 37(1), pp. 243–262.</bibl>
            <idno type="DOI">10.1146/annurev-neuro-071013-014134</idno>
          </bibl>
          <bibl n="7695">
            <bibl>Ciregia, F., Bugliani, M., Ronci, M., Giusti, L., Boldrini, C., Mazzoni, M. R., Mossuto, S., Grano, F., Cnop, M., Marselli, L., Giannaccini, G., Urbani, A., Lucacchini, A. and Marchetti, P. (2017) ‘Palmitate-induced lipotoxicity alters acetylation of multiple proteins in clonal β cells and human pancreatic islets.’, Scientific reports, 7(1), p. 13445.</bibl>
            <idno type="DOI">10.1038/s41598-017-13908-w</idno>
          </bibl>
          <bibl n="7696">
            <bibl>Ciregia, F., Giusti, L., Da Valle, Y., Donadio, E., Consensi, A., Giacomelli, C., Sernissi, F., Scarpellini, P., Maggi, F., Lucacchini, A. and Bazzichi, L. (2013) ‘A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers’, Journal of Translational Medicine, 11(1), p. 243.</bibl>
            <idno type="DOI">10.1186/1479-5876-11-243</idno>
          </bibl>
          <bibl n="7697">deGrauw, T. J., Cecil, K. M., Byars, A. W., Salomons, G. S., Ball, W. S. and Jakobs, C. (2003) ‘The clinical syndrome of creatine transporter deficiency.’, Molecular and cellular biochemistry, 244(1–2), pp. 45–8.</bibl>
          <bibl n="7698">
            <bibl>Depino, A. M. (2013) ‘Peripheral and central inflammation in autism spectrum disorders’, Molecular and Cellular Neuroscience, 53, pp. 69–76</bibl>
            <idno type="DOI">10.1016/j.mcn.2012.10.003</idno>
          </bibl>
          <bibl n="7699">
            <bibl>Di Giovanni, S. and Rathore, K. (2012) ‘p53-dependent pathways in neurite outgrowth and axonal regeneration’, Cell and Tissue Research, 349(1), pp. 87–95.</bibl>
            <idno type="DOI">10.1007/s00441-011-1292-5</idno>
          </bibl>
          <bibl n="7700">
            <bibl>di Salvo, M. L., Mastrangelo, M., Nogu&amp;#233;s, I., Tolve, M., Paiardini, A., Carducci, C., Mei, D., Montomoli, M., Tramonti, A., Guerrini, R., Contestabile, R. and Leuzzi, V. (2017) ‘Pyridoxine-5’-phosphate oxidase (Pnpo) deficiency: Clinical and biochemical alterations associated with the C.347g&amp;amp;gt;A (P.&amp;#183;Arg116gln) mutation.’, Molecular genetics and metabolism. Elsevier, 122(1–2), pp. 135–142.</bibl>
            <idno type="DOI">10.1016/j.ymgme.2017.08.003</idno>
          </bibl>
          <bibl n="7701">
            <bibl>Diaz-Beltran, L., Esteban, F. J. and Wall, D. P. (2016) ‘A common molecular signature in ASD gene expression: following Root 66 to autism’, Translational Psychiatry. Nature Publishing Group, 6(1), pp. e705–e705</bibl>
            <idno type="DOI">10.1038/tp.2015.112</idno>
          </bibl>
          <bibl n="7702">
            <bibl>Dodd, J. R., Birch, N. P., Waldvogel, H. J. and Christie, D. L. (2010) ‘Functional and immunocytochemical characterization of the creatine transporter in rat hippocampal neurons.’, Journal of neurochemistry, 115(3), pp. 684–93.</bibl>
            <idno type="DOI">10.1111/j.1471-4159.2010.06957.x</idno>
          </bibl>
          <bibl n="7703">
            <bibl>Dunlop, R. A., Brunk, U. T. and Rodgers, K. J. (2009) ‘Oxidized proteins: Mechanisms of removal and consequences of accumulation’, IUBMB Life, pp. 522–527.</bibl>
            <idno type="DOI">10.1002/iub.189</idno>
          </bibl>
          <bibl n="7704">
            <bibl>Ebadi, M. and Klangkalya, B. (1979) ‘On the mechanism of pyridoxal phosphate-related convulsions as implicated in enhanced transport of GABA.’, Neuropharmacology, 18(3), pp. 301–7.</bibl>
            <idno type="DOI">10.1016/0028-3908(79)90130-8</idno>
          </bibl>
          <bibl n="7705">
            <bibl>Edvardson, S., Korman, S. H., Livne, A., Shaag, A., Saada, A., Nalbandian, R., Allouche-Arnon, H., Gomori, J. M. and Katz-Brull, R. (2010) ‘l-arginine:glycine amidinotransferase (AGAT) deficiency: Clinical presentation and response to treatment in two patients with a novel mutation’, Molecular Genetics and Metabolism, 101(2–3), pp. 228–232.</bibl>
            <idno type="DOI">10.1016/j.ymgme.2010.06.021</idno>
          </bibl>
          <bibl n="7706">
            <bibl>Enrico, A., Patrizia, G., Luisa, P., Alessandro, P., Gianluigi, L., Carlo, G. and Maurizio, B. (2013) ‘Electrophysiology and biochemical analysis of cyclocreatine uptake and effect in hippocampal slices’, Journal of Integrative Neuroscience, 12(02), pp. 285–297.</bibl>
            <idno type="DOI">10.1142/S0219635213500155</idno>
          </bibl>
          <bibl n="7707">
            <bibl>Etherton, M. R., Blaiss, C. A., Powell, C. M. and Sudhof, T. C. (2009) ‘Mouse neurexin-1  deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments’, Proceedings of the National Academy of Sciences, 106(42), pp. 17998–18003.</bibl>
            <idno type="DOI">10.1073/pnas.0910297106</idno>
          </bibl>
          <bibl n="7708">
            <bibl>Evangeliou, A., Vasilaki, K., Karagianni, P. and Nikolaidis, N. (2009) ‘Clinical applications of creatine supplementation on paediatrics.’, Current pharmaceutical biotechnology, 10(7), pp. 683–90.</bibl>
            <idno type="DOI">10.2174/138920109789542075</idno>
          </bibl>
          <bibl n="7709">
            <bibl>Fons, C., Arias, A., Sempere, A., P&amp;#243;o, P., Pineda, M., Mas, A., L&amp;#243;pez-Sala, A., Garcia-Villoria, J., Vilaseca, M. A., Ozaez, L., Lluch, M., Artuch, R., Campistol, J. and Ribes, A. (2010) ‘Response to creatine analogs in fibroblasts and patients with creatine transporter deficiency’, Molecular Genetics and Metabolism, 99(3), pp. 296–299.</bibl>
            <idno type="DOI">10.1016/j.ymgme.2009.10.186</idno>
          </bibl>
          <bibl n="7710">
            <bibl>Franceschi, C., Bonaf&amp;#232;, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E. and De Benedictis, G. (2006) ‘Inflamm-aging: An Evolutionary Perspective on Immunosenescence’, Annals of the New York Academy of Sciences. Wiley/Blackwell (10.1111), 908(1), pp. 244–254.</bibl>
            <idno type="DOI">10.1111/j.1749-6632.2000.tb06651.x</idno>
          </bibl>
          <bibl n="7711">
            <bibl>Fuccillo, M. V. (2016) ‘Striatal Circuits as a Common Node for Autism Pathophysiology’, Frontiers in Neuroscience, 10, p. 27</bibl>
            <idno type="DOI">10.3389/fnins.2016.00027</idno>
          </bibl>
          <bibl n="7712">Garc&amp;#237;a-Delgado, M., Peral, M. J., Cano, M., Calonge, M. L. and Ilund&amp;#225;in, A. A. (2001) ‘Creatine transport in brush-border membrane vesicles isolated from rat kidney cortex.’, Journal of the American Society of Nephrology : JASN, 12(9), pp. 1819–25.</bibl>
          <bibl n="7713">
            <bibl>Giusti, S. A., Vercelli, C. A., Vogl, A. M., Kolarz, A. W., Pino, N. S., Deussing, J. M. and Refojo, D. (2014) ‘Behavioral phenotyping of Nestin-Cre mice: Implications for genetic mouse models of psychiatric disorders’, Journal of Psychiatric Research, 55, pp. 87–95.</bibl>
            <idno type="DOI">10.1016/j.jpsychires.2014.04.002</idno>
          </bibl>
          <bibl n="7714">Gori, Z., De Tata, V., Pollera, M. and Bergamini, E. (1988) ‘Mitochondrial myopathy in rats fed with a diet containing beta-guanidine propionic acid, an inhibitor of creatine entry in muscle cells.’, British journal of experimental pathology. Wiley-Blackwell, 69(5), pp. 639–50.</bibl>
          <bibl n="7715">
            <bibl>Gospe, S. M., Olin, K. L. and Keen, C. L. (1994) ‘Reduced GABA synthesis in pyridoxine-dependent seizures.’, Lancet (London, England), 343(8906), pp. 1133–4.</bibl>
            <idno type="DOI">10.1016/s0140-6736(94)90236-4</idno>
          </bibl>
          <bibl n="7716">
            <bibl>Grissom, N. M., McKee, S. E., Schoch, H., Bowman, N., Havekes, R., O’Brien, W. T., Mahrt, E., Siegel, S., Commons, K., Portfors, C., Nickl-Jockschat, T., Reyes, T. M. and Abel, T. (2018) ‘Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders’, Molecular Psychiatry, 23(3), pp. 544–555.</bibl>
            <idno type="DOI">10.1038/mp.2017.184</idno>
          </bibl>
          <bibl n="7717">Guimbal, C. and Kilimann, M. W. (1993) ‘A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. cDNA cloning and functional expression.’, The Journal of biological chemistry, 268(12), pp. 8418–21.</bibl>
          <bibl n="7718">Haffernan, C. (2015) Creatine: a short history</bibl>
          <bibl n="7719">
            <bibl>Hathaway, S. C., Friez, M., Limbo, K., Parker, C., Salomons, G. S., Vockley, J., Wood, T. and Abdul-Rahman, O. A. (2010) ‘X-Linked Creatine Transporter Deficiency Presenting as a Mitochondrial Disorder’, Journal of Child Neurology, 25(8), pp. 1009–1012.</bibl>
            <idno type="DOI">10.1177/0883073809352109</idno>
          </bibl>
          <bibl n="7720">
            <bibl>Head, E., Lott, I. T., Wilcock, D. M. and Lemere, C. A. (2016) ‘Aging in Down Syndrome and the Development of Alzheimer’s Disease Neuropathology.’, Current Alzheimer research, 13(1), pp. 18–29.</bibl>
            <idno type="DOI">10.2174/1567205012666151020114607</idno>
          </bibl>
          <bibl n="7721">
            <bibl>Hefendehl, J. K., Neher, J. J., S&amp;#252;hs, R. B., Kohsaka, S., Skodras, A. and Jucker, M. (2014) ‘Homeostatic and injury-induced microglia behavior in the aging brain’, Aging Cell. Wiley/Blackwell (10.1111), 13(1), pp. 60–69.</bibl>
            <idno type="DOI">10.1111/acel.12149</idno>
          </bibl>
          <bibl n="7722">
            <bibl>Hoffmann, H. and Schiene-Fischer, C. (2014) ‘Functional aspects of extracellular cyclophilins’, Biological Chemistry, 395(7–8), pp. 721–35.</bibl>
            <idno type="DOI">10.1515/hsz-2014-0125</idno>
          </bibl>
          <bibl n="7723">
            <bibl>H&amp;#246;hn, A. and Grune, T. (2013) ‘Lipofuscin: formation, effects and role of macroautophagy.’, Redox biology. Elsevier, 1(1), pp. 140–4.</bibl>
            <idno type="DOI">10.1016/j.redox.2013.01.006</idno>
          </bibl>
          <bibl n="7724">
            <bibl>Ippolito, D. M. and Eroglu, C. (2010) ‘Quantifying Synapses: an Immunocytochemistry-based Assay to Quantify Synapse Number’, Journal of Visualized Experiments, (45)</bibl>
            <idno type="DOI">10.3791/2270</idno>
          </bibl>
          <bibl n="7725">
            <bibl>Ishioka, N., Sato, J., Nakamura, J., Ohkubo, T., Takeda, A. and Kurioka, S. (1995) ‘In vivo modification of GABAA receptor with a high dose of pyridoxal phosphate induces tonic-clonic convulsion in immature mice.’, Neurochemistry international, 26(4), pp. 369–73.</bibl>
            <idno type="DOI">10.1016/0197-0186(94)00145-k</idno>
          </bibl>
          <bibl n="7726">
            <bibl>Item, C. B., St&amp;#246;ckler-Ipsiroglu, S., Stromberger, C., M&amp;#252;hl, A., Alessandr&amp;#236;, M. G., Bianchi, M. C., Tosetti, M., Fornai, F. and Cioni, G. (2001) ‘Arginine:Glycine Amidinotransferase Deficiency: The Third Inborn Error of Creatine Metabolism in Humans’, The American Journal of Human Genetics, 69(5), pp. 1127–1133.</bibl>
            <idno type="DOI">10.1086/323765</idno>
          </bibl>
          <bibl n="7727">
            <bibl>Iyer, G. S., Krahe, R., Goodwin, L. A., Doggett, N. A., Siciliano, M. J., Funanage, V. L. and Proujansky, R. (1996) ‘Identification of a testis-expressed creatine transporter gene at 16p11.2 and confirmation of the X-linked locus to Xq28.’, Genomics, 34(1), pp. 143–6</bibl>
            <idno type="DOI">10.1006/geno.1996.0254</idno>
          </bibl>
          <bibl n="7728">Joncquel-Chevalier Curt, M., Voicu, P. M., Fontaine, M., Dessein, A. F., Porchet, N., Mention-Mulliez, K., Dobbelaere, D., Soto-Ares, G., Cheillan, D. and Vamecq, J. (2015) ‘Creatine biosynthesis and transport in health and disease’, Biochimie, 119, pp. 146–165.</bibl>
          <bibl n="7729">
            <bibl>Kaidanovich-Beilin, O., Lipina, T., Vukobradovic, I., Roder, J. and Woodgett, J. R. (2011) ‘Assessment of Social Interaction Behaviors’, Journal of Visualized Experiments, (48).</bibl>
            <idno type="DOI">10.3791/2473</idno>
          </bibl>
          <bibl n="7730">
            <bibl>Kalkman, H. O. (2012) ‘Potential opposite roles of the extracellular signal-regulated kinase (ERK) pathway in autism spectrum and bipolar disorders’, Neuroscience &amp;amp; Biobehavioral Reviews, 36(10), pp. 2206–2213.</bibl>
            <idno type="DOI">10.1016/j.neubiorev.2012.07.008</idno>
          </bibl>
          <bibl n="7731">
            <bibl>Kempermann, G. (2015) ‘Activity Dependency and Aging in the Regulation of Adult Neurogenesis’, Cold Spring Harbor Perspectives in Biology, 7(11), p. a018929.</bibl>
            <idno type="DOI">10.1101/cshperspect.a018929</idno>
          </bibl>
          <bibl n="7732">
            <bibl>Kopra, O., Vesa, J., von Schantz, C., Manninen, T., Minye, H., Fabritius, A.-L., Rapola, J., Diggelen, O. P. van, Saarela, J., Jalanko, A. and Peltonen, L. (2004) ‘A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging’, Human Molecular Genetics, 13(23), pp. 2893–2906</bibl>
            <idno type="DOI">10.1093/hmg/ddh312</idno>
          </bibl>
          <bibl n="7733">
            <bibl>Kristensen, A. S., Andersen, J., J&amp;#248;rgensen, T. N., S&amp;#248;rensen, L., Eriksen, J., Loland, C. J., Str&amp;#248;mgaard, K. and Gether, U. (2011) ‘SLC6 neurotransmitter transporters: structure, function, and regulation.’, Pharmacological reviews, 63(3), pp. 585–640.</bibl>
            <idno type="DOI">10.1124/pr.108.000869</idno>
          </bibl>
          <bibl n="7734">
            <bibl>Kuiper, J. W., Oerlemans, F. T., Fransen, J. A. and Wieringa, B. (2008) ‘Creatine kinase B deficient neurons exhibit an increased fraction of motile mitochondria’, BMC Neuroscience, 9(1), p. 73</bibl>
            <idno type="DOI">10.1186/1471-2202-9-73</idno>
          </bibl>
          <bibl n="7735">
            <bibl>Kurosawa, Y., DeGrauw, T. J., Lindquist, D. M., Blanco, V. M., Pyne-Geithman, G. J., Daikoku, T., Chambers, J. B., Benoit, S. C. and Clark, J. F. (2012) ‘Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency’, Journal of Clinical Investigation, 122(8), pp. 2837–2846.</bibl>
            <idno type="DOI">10.1172/JCI59373</idno>
          </bibl>
          <bibl n="7736">
            <bibl>Lahiri, D. K., Sokol, D. K., Erickson, C., Ray, B., Ho, C. Y. and Maloney, B. (2013) ‘Autism as early neurodevelopmental disorder: evidence for an sAPPα-mediated anabolic pathway’, Frontiers in Cellular Neuroscience, 7.</bibl>
            <idno type="DOI">10.3389/fncel.2013.00094</idno>
          </bibl>
          <bibl n="7737">
            <bibl>Lawler, J. M., Barnes, W. S., Wu, G., Song, W. and Demaree, S. (2002) ‘Direct Antioxidant Properties of Creatine’, Biochemical and Biophysical Research Communications, 290(1), pp. 47–52.</bibl>
            <idno type="DOI">10.1006/bbrc.2001.6164</idno>
          </bibl>
          <bibl n="7738">
            <bibl>Lee, S. W., Clemenson, G. D. and Gage, F. H. (2012) ‘New neurons in an aged brain’, Behavioural Brain Research, 227(2), pp. 497–507.</bibl>
            <idno type="DOI">10.1016/j.bbr.2011.10.009</idno>
          </bibl>
          <bibl n="7739">
            <bibl>Leuzzi, V., Alessandr&amp;#236;, M. G., Casarano, M., Battini, R. and Cioni, G. (2008) ‘Arginine and glycine stimulate creatine synthesis in creatine transporter 1-deficient lymphoblasts’, Analytical Biochemistry, 375(1), pp. 153–155.</bibl>
            <idno type="DOI">10.1016/j.ab.2008.01.018</idno>
          </bibl>
          <bibl n="7740">
            <bibl>Leuzzi, V., Bianchi, M. C., Tosetti, M., Carducci, C., Cerquiglini, C. A., Cioni, G. and Antonozzi, I. (2000) ‘Brain creatine depletion: guanidinoacetate methyltransferase deficiency (improving with creatine supplementation).’, Neurology, 55(9), pp. 1407–9.</bibl>
            <idno type="DOI">10.1212/wnl.55.9.1407</idno>
          </bibl>
          <bibl n="7741">
            <bibl>Leuzzi, V., Mastrangelo, M., Battini, R. and Cioni, G. (2013) ‘Inborn errors of creatine metabolism and epilepsy’, Epilepsia, 54(2), pp. 217–227.</bibl>
            <idno type="DOI">10.1111/epi.12020</idno>
          </bibl>
          <bibl n="7742">
            <bibl>Levillain, O., Marescau, B. and Deyn, P. P. de (1995) ‘Guanidino compound metabolism in rats subjected to 20% to 90% nephrectomy’, Kidney International. Elsevier, 47(2), pp. 464–472.</bibl>
            <idno type="DOI">10.1038/KI.1995.59</idno>
          </bibl>
          <bibl n="7743">
            <bibl>Li, H., Thali, R. F., Smolak, C., Gong, F., Alzamora, R., Wallimann, T., Scholz, R., Pastor-Soler, N. M., Neumann, D. and Hallows, K. R. (2010) ‘Regulation of the creatine transporter by AMP-activated protein kinase in kidney epithelial cells.’, American journal of physiology. Renal physiology. American Physiological Society, 299(1), pp. F167-77.</bibl>
            <idno type="DOI">10.1152/ajprenal.00162.2010</idno>
          </bibl>
          <bibl n="7744">
            <bibl>Lipton, J. O. and Sahin, M. (2014) ‘The Neurology of mTOR’, Neuron. Elsevier Inc., 84(2), pp. 275–291.</bibl>
            <idno type="DOI">10.1016/j.neuron.2014.09.034</idno>
          </bibl>
          <bibl n="7745">
            <bibl>Loike, J. D., Zalutsky, D. L., Kaback, E., Miranda, A. F. and Silverstein, S. C. (1988) ‘Extracellular creatine regulates creatine transport in rat and human muscle cells.’, Proceedings of the National Academy of Sciences of the United States of America, 85(3), pp. 807–11</bibl>
            <idno type="DOI">10.1073/pnas.85.3.807</idno>
          </bibl>
          <bibl n="7746">
            <bibl>Lonetti, G., Angelucci, A., Morando, L., Boggio, E. M., Giustetto, M. and Pizzorusso, T. (2010) ‘Early Environmental Enrichment Moderates the Behavioral and Synaptic Phenotype of MeCP2 Null Mice’, Biological Psychiatry, 67(7), pp. 657–665.</bibl>
            <idno type="DOI">10.1016/j.biopsych.2009.12.022</idno>
          </bibl>
          <bibl n="7747">
            <bibl>Lunardi, G., Parodi, A., Perasso, L., Pohvozcheva, A. V., Scarrone, S., Adriano, E., Florio, T., Gandolfo, C., Cupello, A., Burov, S. V. and Balestrino, M. (2006) ‘The creatine transporter mediates the uptake of creatine by brain tissue, but not the uptake of two creatine-derived compounds’, Neuroscience, 142(4), pp. 991–997.</bibl>
            <idno type="DOI">10.1016/j.neuroscience.2006.06.058</idno>
          </bibl>
          <bibl n="7748">
            <bibl>Maccarinelli, F., Pagani, A., Cozzi, A., Codazzi, F., Di Giacomo, G., Capoccia, S., Rapino, S., Finazzi, D., Politi, L. S., Cirulli, F., Giorgio, M., Cremona, O., Grohovaz, F. and Levi, S. (2015) ‘A novel neuroferritinopathy mouse model (FTL 498InsTC) shows progressive brain iron dysregulation, morphological signs of early neurodegeneration and motor coordination deficits’, Neurobiology of Disease, 81, pp. 119–133.</bibl>
            <idno type="DOI">10.1016/j.nbd.2014.10.023</idno>
          </bibl>
          <bibl n="7749">
            <bibl>Matt, S. M. and Johnson, R. W. (2016) ‘Neuro-immune dysfunction during brain aging: new insights in microglial cell regulation’, Current Opinion in Pharmacology, 26, pp. 96–101.</bibl>
            <idno type="DOI">10.1016/j.coph.2015.10.009</idno>
          </bibl>
          <bibl n="7750">
            <bibl>Matthews, R. T., Ferrante, R. J., Klivenyi, P., Yang, L., Klein, A. M., Mueller, G., Kaddurah-Daouk, R. and Beal, M. F. (1999) ‘Creatine and Cyclocreatine Attenuate MPTP Neurotoxicity’, Experimental Neurology, 157(1), pp. 142–149.</bibl>
            <idno type="DOI">10.1006/exnr.1999.7049</idno>
          </bibl>
          <bibl n="7751">
            <bibl>McFarlane, H. G., Kusek, G. K., Yang, M., Phoenix, J. L., Bolivar, V. J. and Crawley, J. N. (2008) ‘Autism-like behavioral phenotypes in BTBR T+tf/J mice’, Genes, Brain and Behavior, 7(2), pp. 152–163.</bibl>
            <idno type="DOI">10.1111/j.1601-183X.2007.00330.x</idno>
          </bibl>
          <bibl n="7752">
            <bibl>McQuail, J. A., Frazier, C. J. and Bizon, J. L. (2015) ‘Molecular aspects of age-related cognitive decline: the role of GABA signaling’, Trends in Molecular Medicine, 21(7), pp. 450–460.</bibl>
            <idno type="DOI">10.1016/j.molmed.2015.05.002</idno>
          </bibl>
          <bibl n="7753">
            <bibl>Mercimek-Mahmutoglu, S., Connolly, M. B., Poskitt, K. J., Horvath, G. A., Lowry, N., Salomons, G. S., Casey, B., Sinclair, G., Davis, C., Jakobs, C. and Stockler-Ipsiroglu, S. (2010) ‘Treatment of intractable epilepsy in a female with SLC6A8 deficiency’, Molecular Genetics and Metabolism, 101(4), pp. 409–412.</bibl>
            <idno type="DOI">10.1016/j.ymgme.2010.08.016</idno>
          </bibl>
          <bibl n="7754">
            <bibl>Mercimek-Mahmutoglu, S., Stoeckler-Ipsiroglu, S., Adami, A., Appleton, R., Araujo, H. C., Duran, M., Ensenauer, R., Fernandez-Alvarez, E., Garcia, P., Grolik, C., Item, C. B., Leuzzi, V., Marquardt, I., Muhl, A., Saelke-Kellermann, R. A., Salomons, G. S., Schulze, A., Surtees, R., van der Knaap, M. S., Vasconcelos, R., Verhoeven, N. M., Vilarinho, L., Wilichowski, E. and Jakobs, C. (2006) ‘GAMT deficiency: Features, treatment, and outcome in an inborn error of creatine synthesis’, Neurology, 67(3), pp. 480–484.</bibl>
            <idno type="DOI">10.1212/01.wnl.0000234852.43688.bf</idno>
          </bibl>
          <bibl n="7755">
            <bibl>Moy, S. S., Nadler, J. J., Perez, A., Barbaro, R. P., Johns, J. M., Magnuson, T. R., Piven, J. and Crawley, J. N. (2004) ‘Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice’, Genes, Brain and Behavior, 3(5), pp. 287–302.</bibl>
            <idno type="DOI">10.1111/j.1601-1848.2004.00076.x</idno>
          </bibl>
          <bibl n="7756">
            <bibl>Nabuurs, C. I., Choe, C. U., Veltien, A., Kan, H. E., van Loon, L. J. C., Rodenburg, R. J. T., Matschke, J., Wieringa, B., Kemp, G. J., Isbrandt, D. and Heerschap, A. (2013) ‘Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake’, The Journal of Physiology, 591(2), pp. 571–592.</bibl>
            <idno type="DOI">10.1113/jphysiol.2012.241760</idno>
          </bibl>
          <bibl n="7757">Nash, S. R., Giros, B., Kingsmore, S. F., Rochelle, J. M., Suter, S. T., Gregor, P., Seldin, M. F. and Caron, M. G. (1994) ‘Cloning, pharmacological characterization, and genomic localization of the human creatine transporter.’, Receptors &amp;amp; channels, 2(2), pp. 165–74.</bibl>
          <bibl n="7758">
            <bibl>Ndika, J. D. T., Johnston, K., Barkovich, J. A., Wirt, M. D., O’Neill, P., Betsalel, O. T., Jakobs, C. and Salomons, G. S. (2012) ‘Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency’, Molecular Genetics and Metabolism, 106(1), pp. 48–54.</bibl>
            <idno type="DOI">10.1016/j.ymgme.2012.01.017</idno>
          </bibl>
          <bibl n="7759">
            <bibl>Nicolas, M. and Hassan, B. A. (2014) ‘Amyloid precursor protein and neural development’, Development, 141(13), pp. 2543–2548.</bibl>
            <idno type="DOI">10.1242/dev.108712</idno>
          </bibl>
          <bibl n="7760">
            <bibl>Nigro, P., Pompilio, G. and Capogrossi, M. C. (2013) ‘Cyclophilin A: a key player for human disease’, Cell Death &amp;amp; Disease, 4(10), pp. e888–e888.</bibl>
            <idno type="DOI">10.1038/cddis.2013.410</idno>
          </bibl>
          <bibl n="7761">
            <bibl>Nota, B., Ndika, J. D. T., van de Kamp, J. M., Kanhai, W. A., van Dooren, S. J. M., van de Wiel, M. A., Pals, G. and Salomons, G. S. (2014) ‘RNA Sequencing of Creatine Transporter (SLC6A8) Deficient Fibroblasts Reveals Impairment of the Extracellular Matrix’, Human Mutation, 35(9), pp. 1128–1135</bibl>
            <idno type="DOI">10.1002/humu.22609</idno>
          </bibl>
          <bibl n="7762">
            <bibl>Nouioua, S., Cheillan, D., Zaouidi, S., Salomons, G. S., Amedjout, N., Kessaci, F., Bou-lahdour, N., Hamadouche, T. and Tazir, M. (2013) ‘Creatine deficiency syndrome. A treatable myopathy due to arginine–glycine amidinotransferase (AGAT) defi-ciency’, Neuromuscular Disorders, 23(8), pp. 670–674.</bibl>
            <idno type="DOI">10.1016/j.nmd.2013.04.011</idno>
          </bibl>
          <bibl n="7763">
            <bibl>O’Gorman, E., Beutner, G., Dolder, M., Koretsky, A. P., Brdiczka, D. and Wallimann, T. (1997) ‘The role of creatine kinase in inhibition of mitochondrial permeability transition’, FEBS Letters. No longer published by Elsevier, 414(2), pp. 253–257.</bibl>
            <idno type="DOI">10.1016/S0014-5793(97)01045-4</idno>
          </bibl>
          <bibl n="7764">
            <bibl>Papale, A., d’Isa, R., Menna, E., Cerovic, M., Solari, N., Hardingham, N., Cambiaghi, M., Cursi, M., Barbacid, M., Leocani, L., Fasano, S., Matteoli, M. and Brambilla, R. (2017) ‘Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies’, Biological Psychiatry, 81(3), pp. 179–192.</bibl>
            <idno type="DOI">10.1016/j.biopsych.2016.06.016</idno>
          </bibl>
          <bibl n="7765">
            <bibl>Peral, M. J., V&amp;#225;zquez-Carretero, M. D. and Ilundain, A. A. (2010) ‘Na+/Cl−/creatine transporter activity and expression in rat brain synaptosomes’, Neuroscience, 165(1), pp. 53–60.</bibl>
            <idno type="DOI">10.1016/j.neuroscience.2009.10.001</idno>
          </bibl>
          <bibl n="7766">
            <bibl>Perasso, L., Adriano, E., Ruggeri, P., Burov, S. V., Gandolfo, C. and Balestrino, M. (2009) ‘In vivo neuroprotection by a creatine-derived compound: Phosphocreatine–Mg-complex acetate’, Brain Research, 1285, pp. 158–163.</bibl>
            <idno type="DOI">10.1016/j.brainres.2009.06.009</idno>
          </bibl>
          <bibl n="7767">
            <bibl>Perasso, L., Cupello, A., Lunardi, G. L., Principato, C., Gandolfo, C. and Balestrino, M. (2003) ‘Kinetics of creatine in blood and brain after intraperitoneal injection in the rat.’, Brain research, 974(1–2), pp. 37–42.</bibl>
            <idno type="DOI">10.1016/s0006-8993(03)02547-2</idno>
          </bibl>
          <bibl n="7768">
            <bibl>Perna, M. K., Kokenge, A. N., Miles, K. N., Udobi, K. C., Clark, J. F., Pyne-Geithman, G. J., Khuchua, Z. and Skelton, M. R. (2016) ‘Creatine transporter deficiency leads to increased whole body and cellular metabolism’, Amino Acids. Springer Vienna.</bibl>
            <idno type="DOI">10.1007/s00726-016-2291-3</idno>
          </bibl>
          <bibl n="7769">
            <bibl>P&amp;#243;o-Arg&amp;#252;elles, P., Arias, A., Vilaseca, M. A., Ribes, A., Artuch, R., Sans-Fito, A., Moreno, A., Jakobs, C. and Salomons, G. (2006) ‘X-Linked creatine transporter deficiency in two patients with severe mental retardation and autism’, Journal of Inherited Metabolic Disease, 29(1), pp. 220–223.</bibl>
            <idno type="DOI">10.1007/s10545-006-0212-4</idno>
          </bibl>
          <bibl n="7770">
            <bibl>Pucilowska, J., Vithayathil, J., Pagani, M., Kelly, C., Karlo, J. C., Robol, C., Morella, I., Gozzi, A., Brambilla, R. and Landreth, G. E. (2018) ‘Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice’, The Journal of Neuroscience, 38(30), pp. 6640–6652.</bibl>
            <idno type="DOI">10.1523/JNEUROSCI.0515-17.2018</idno>
          </bibl>
          <bibl n="7771">
            <bibl>Pucilowska, J., Vithayathil, J., Tavares, E. J., Kelly, C., Karlo, J. C. and Landreth, G. E. (2015) ‘The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway’, Journal of Neuroscience, 35(7), pp. 3190–3200.</bibl>
            <idno type="DOI">10.1523/JNEUROSCI.4864-13.2015</idno>
          </bibl>
          <bibl n="7772">
            <bibl>Puusepp, H., Kall, K., Salomons, G. S., Talvik, I., M&amp;#228;nnamaa, M., Rein, R., Jakobs, C. and &amp;#213;unap, K. (2010) ‘The screening of SLC6A8 deficiency among Estonian families with X-linked mental retardation.’, Journal of inherited metabolic disease, 33 Suppl 3, pp. S5-11.</bibl>
            <idno type="DOI">10.1007/s10545-008-1063-y</idno>
          </bibl>
          <bibl n="7773">
            <bibl>Pyne-Geithman, G. J., deGrauw, T. J., Cecil, K. M., Chuck, G., Lyons, M. A., Ishida, Y. and Clark, J. F. (2004) ‘Presence of normal creatine in the muscle of a patient with a mutation in the creatine transporter: a case study.’, Molecular and cellular biochemistry, 262(1–2), pp. 35–9.</bibl>
            <idno type="DOI">10.1023/b:mcbi.0000038213.15646.4a</idno>
          </bibl>
          <bibl n="7774">
            <bibl>Rao, J. S., Kellom, M., Kim, H.-W., Rapoport, S. I. and Reese, E. A. (2012) ‘Neuroinflammation and Synaptic Loss’, Neurochemical Research, 37(5), pp. 903–910.</bibl>
            <idno type="DOI">10.1007/s11064-012-0708-2</idno>
          </bibl>
          <bibl n="7775">
            <bibl>Ratto, G. M. and Pizzorusso, T. (2006) ‘A Kinase with a Vision’, in Brain Repair. Boston, MA: Springer US, pp. 122–132.</bibl>
            <idno type="DOI">10.1007/0-387-30128-3_7</idno>
          </bibl>
          <bibl n="7776">
            <bibl>Ray, B., Long, J. M., Sokol, D. K. and Lahiri, D. K. (2011) ‘Increased Secreted Amyloid Precursor Protein-α (sAPPα) in Severe Autism: Proposal of a Specific, Anabolic Pathway and Putative Biomarker’, PLoS ONE. Edited by A. I. Bush, 6(6), p. e20405.</bibl>
            <idno type="DOI">10.1371/journal.pone.0020405</idno>
          </bibl>
          <bibl n="7777">
            <bibl>Rothwell, P. E., Fuccillo, M. V., Maxeiner, S., Hayton, S. J., Gokce, O., Lim, B. K., Fowler, S. C., Malenka, R. C. and S&amp;#252;dhof, T. C. (2014) ‘Autism-Associated Neuroligin-3 Mutations Commonly Impair Striatal Circuits to Boost Repetitive Behaviors’, Cell, 158(1), pp. 198–212</bibl>
            <idno type="DOI">10.1016/j.cell.2014.04.045</idno>
          </bibl>
          <bibl n="7778">
            <bibl>Russell, A. P., Ghobrial, L., Wright, C. R., Lamon, S., Brown, E. L., Kon, M., Skelton, M. R. and Snow, R. J. (2014) ‘Creatine transporter (SLC6A8) knockout mice display an increased capacity for in vitro creatine biosynthesis in skeletal muscle’, Frontiers in Physiology. Frontiers, 5, p. 314</bibl>
            <idno type="DOI">10.3389/fphys.2014.00314</idno>
          </bibl>
          <bibl n="7779">
            <bibl>Ryan, S. M. and Nolan, Y. M. (2016) ‘Neuroinflammation negatively affects adult hippocampal neurogenesis and cognition: can exercise compensate?’, Neuroscience &amp;amp; Biobehavioral Reviews, 61, pp. 121–131</bibl>
            <idno type="DOI">10.1016/j.neubiorev.2015.12.004</idno>
          </bibl>
          <bibl n="7780">
            <bibl>Salomons, G. S., van Dooren, S. J. M., Verhoeven, N. M., Cecil, K. M., Ball, W. S., Degrauw, T. J. and Jakobs, C. (2001) ‘X-Linked Creatine-Transporter Gene (SLC6A8) Defect: A New Creatine-Deficiency Syndrome’, The American Journal of Human Genetics, 68(6), pp. 1497–1500.</bibl>
            <idno type="DOI">10.1086/320595</idno>
          </bibl>
          <bibl n="7781">
            <bibl>Saunders, A., Macosko, E., Wysoker, A., Goldman, M., Krienen, F., Bien, E., Baum, M., Wang, S., Goeva, A., Nemesh, J., Kamitaki, N., Brumbaugh, S., Kulp, D. and McCarroll, S. A. (2018) ‘A Single-Cell Atlas of Cell Types, States, and Other Transcriptional Patterns from Nine Regions of the Adult Mouse Brain’, bioRxiv. Cold Spring Harbor Laboratory, p. 299081</bibl>
            <idno type="DOI">10.1101/299081</idno>
          </bibl>
          <bibl n="7782">
            <bibl>Schiaffino, M. C., Bellini, C., Costabello, L., Caruso, U., Jakobs, C., Salomons, G. S. and Bonioli, E. (2005) ‘X-linked creatine transporter deficiency’, Neurogenetics, 6(3), pp. 165–168.</bibl>
            <idno type="DOI">10.1007/s10048-005-0002-4</idno>
          </bibl>
          <bibl n="7783">
            <bibl>Sestili, P., Martinelli, C., Colombo, E., Barbieri, E., Potenza, L., Sartini, S. and Fimognari, C. (2011) ‘Creatine as an antioxidant’, Amino Acids, 40(5), pp. 1385–1396.</bibl>
            <idno type="DOI">10.1007/s00726-011-0875-5</idno>
          </bibl>
          <bibl n="7784">
            <bibl>Shaw, A. E. and Bamburg, J. R. (2017) ‘Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders’, Pharmacology &amp;amp; Therapeutics, 175, pp. 17–27.</bibl>
            <idno type="DOI">10.1016/j.pharmthera.2017.02.031</idno>
          </bibl>
          <bibl n="7785">
            <bibl>Sherwin, E., Dinan, T. G. and Cryan, J. F. (2018) ‘Recent developments in understanding the role of the gut microbiota in brain health and disease’, Annals of the New York Academy of Sciences, 1420(1), pp. 5–25</bibl>
            <idno type="DOI">10.1111/nyas.13416</idno>
          </bibl>
          <bibl n="7786">Shetty, A. K. and Turner, D. A. (1998) ‘Hippocampal interneurons expressing glutamic acid decarboxylase and calcium-binding proteins decrease with aging in Fischer 344 rats.’, The Journal of comparative neurology, 394(2), pp. 252–69.</bibl>
          <bibl n="7787">
            <bibl>Shi, L., Argenta, A. E., Winseck, A. K. and Brunso-Bechtold, J. K. (2004) ‘Stereological quantification of GAD-67-immunoreactive neurons and boutons in the hippocampus of middle-aged and old Fischer 344 &amp;#215; Brown Norway rats’, Journal of Comparative Neurology, 478(3), pp. 282–291.</bibl>
            <idno type="DOI">10.1002/cne.20303</idno>
          </bibl>
          <bibl n="7788">
            <bibl>Sierra, A., Beccari, S., Diaz-Aparicio, I., Encinas, J. M., Comeau, S. and Tremblay, M.-&amp;#200;. (2014) ‘Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis’, Neural Plasticity, 2014, pp. 1–15</bibl>
            <idno type="DOI">10.1155/2014/610343</idno>
          </bibl>
          <bibl n="7789">
            <bibl>Silingardi, D., Angelucci, A., De Pasquale, R., Borsotti, M., Squitieri, G., Brambilla, R., Putignano, E., Pizzorusso, T. and Berardi, N. (2011) ‘ERK pathway activation bidirectionally affects visual recognition memory and synaptic plasticity in the perirhinal cortex.’, Frontiers in behavioral neuroscience. Frontiers Media SA, 5, p. 84.</bibl>
            <idno type="DOI">10.3389/fnbeh.2011.00084</idno>
          </bibl>
          <bibl n="7790">
            <bibl>Skelton, M. R., Schaefer, T. L., Graham, D. L., deGrauw, T. J., Clark, J. F., Williams, M. T. and Vorhees, C. V. (2011) ‘Creatine Transporter (CrT; Slc6a8) Knockout Mice as a Model of Human CrT Deficiency’, PLoS ONE. Edited by E. M. C. Skoulakis. Public Library of Science, 6(1), p. e16187.</bibl>
            <idno type="DOI">10.1371/journal.pone.0016187</idno>
          </bibl>
          <bibl n="7791">
            <bibl>St&amp;#246;ckler, S., Hanefeld, F. and Frahm, J. (1996) ‘Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism.’, Lancet (London, England), 348(9030), pp. 789–90.</bibl>
            <idno type="DOI">10.1016/s0140-6736(96)04116-5</idno>
          </bibl>
          <bibl n="7792">
            <bibl>St&amp;#246;ckler, S., Holzbach, U., Hanefeld, F., Marquardt, I., Helms, G., Requart, M., H&amp;#228;nicke, W. and Frahm, J. (1994) ‘Creatine deficiency in the brain: a new, treatable inborn error of metabolism.’, Pediatric research, 36(3), pp. 409–413.</bibl>
            <idno type="DOI">10.1203/00006450-199409000-00023</idno>
          </bibl>
          <bibl n="7793">
            <bibl>Sullivan, P. G., Geiger, J. D., Mattson, M. P. and Scheff, S. W. (2000) ‘Dietary supplement creatine protects against traumatic brain injury.’, Annals of neurology, 48(5), pp. 723–9.</bibl>
            <idno type="DOI">10.1111/j.1460-9568.2004.03478.x</idno>
          </bibl>
          <bibl n="7794">
            <bibl>Terman, A. and Brunk, U. T. (2006) ‘Oxidative Stress, Accumulation of Biological “Garbage”, and Aging’, Antioxidants &amp;amp; Redox Signaling, 8(1–2), pp. 197–204.</bibl>
            <idno type="DOI">10.1089/ars.2006.8.197</idno>
          </bibl>
          <bibl n="7795">
            <bibl>Thomas, G. M. and Huganir, R. L. (2004) ‘MAPK cascade signalling and synaptic plasticity’, Nature Reviews Neuroscience, 5(3), pp. 173–183.</bibl>
            <idno type="DOI">10.1038/nrn1346</idno>
          </bibl>
          <bibl n="7796">
            <bibl>Torremans, A., Marescau, B., Possemiers, I., Van Dam, D., D’Hooge, R., Isbrandt, D. and De Deyn, P. P. (2005) ‘Biochemical and behavioural phenotyping of a mouse model for GAMT deficiency’, Journal of the Neurological Sciences, 231(1–2), pp. 49–55</bibl>
            <idno type="DOI">10.1016/j.jns.2004.12.014</idno>
          </bibl>
          <bibl n="7797">
            <bibl>Tronche, F., Kellendonk, C., Kretz, O., Gass, P., Anlag, K., Orban, P. C., Bock, R., Klein, R. and Sch&amp;#252;tz, G. (1999) ‘Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety’, Nature Genetics, 23(1), pp. 99–103.</bibl>
            <idno type="DOI">10.1038/12703</idno>
          </bibl>
          <bibl n="7798">
            <bibl>Udobi, K. C., Kokenge, A. N., Hautman, E. R., Ullio, G., Coene, J., Williams, M. T., Vorhees, C. V., Mabondzo, A. and Skelton, M. R. (2018) ‘Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8’, Genes, Brain and Behavior, 17(6), p. e12461.</bibl>
            <idno type="DOI">10.1111/gbb.12461</idno>
          </bibl>
          <bibl n="7799">
            <bibl>van de Kamp, J. M., Jakobs, C., Gibson, K. M. and Salomons, G. S. (2013) ‘New insights into creatine transporter deficiency: the importance of recycling creatine in the brain’, Journal of Inherited Metabolic Disease, 36(1), pp. 155–156.</bibl>
            <idno type="DOI">10.1007/s10545-012-9537-3</idno>
          </bibl>
          <bibl n="7800">
            <bibl>van de Kamp, J. M., Mancini, G. M. and Salomons, G. S. (2014) ‘X-linked creatine transporter deficiency: clinical aspects and pathophysiology’, Journal of Inherited Metabolic Disease, 37(5), pp. 715–733.</bibl>
            <idno type="DOI">10.1007/s10545-014-9713-8</idno>
          </bibl>
          <bibl n="7801">
            <bibl>van de Kamp, J., Betsalel, O. T., Mercimek-Mahmutoglu, S., Abulhoul, L., Gr&amp;#252;newald, S., Anselm, I., Azzouz, H., Bratkovic, D., de Brouwer, A., Hamel, B., Kleefstra, T., Yntema, H., Campistol, J., Vilaseca, M. A., Cheillan, D., D’Hooghe, M., Diogo, L., Garcia, P., Valongo, C., Fonseca, M., Frints, S., Wilcken, B., von der Haar, S., Meijers-Heijboer, H. E., Hofstede, F., Johnson, D., Kant, S. G., Lion-Francois, L., Pitelet, G., Longo, N., Maat-Kievit, J. A., Monteiro, J. P., Munnich, A., Muntau, A. C., Nassogne, M. C., Osaka, H., Ounap, K., Pinard, J. M., Quijano-Roy, S., Poggenburg, I., Poplawski, N., Abdul-Rahman, O., Ribes, A., Arias, A., Yaplito-Lee, J., Schulze, A., Schwartz, C. E., Schwenger, S., Soares, G., Sznajer, Y., Valayannopoulos, V., Van Esch, H., Waltz, S., Wamelink, M. M. C., Pouwels, P. J. W., Errami, A., van der Knaap, M. S., Jakobs, C., Mancini, G. M. and Salomons, G. S. (2013) ‘Phenotype and genotype in 101 males with X-linked creatine transporter deficiency’, Journal of Medical Genetics, 50(7), pp. 463–472.</bibl>
            <idno type="DOI">10.1136/jmedgenet-2013-101658</idno>
          </bibl>
          <bibl n="7802">
            <bibl>van de Kamp, J., Errami, A., Howidi, M., Anselm, I., Winter, S., Phalin-Roque, J., Osaka, H., van Dooren, S. J. M., Mancini, G. M., Steinberg, S. J. and Salomons, G. S. (2015) ‘Genotype-phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1’, Clinical Genetics, 87(2), pp. 141–147.</bibl>
            <idno type="DOI">10.1111/cge.12355</idno>
          </bibl>
          <bibl n="7803">
            <bibl>van de Kamp, J., Mancini, G., Pouwels, P., Betsalel, O., van Dooren, S., de Koning, I., Steenweg, M., Jakobs, C., van der Knaap, M. and Salomons, G. (2011) ‘Clinical features and X-inactivation in females heterozygous for creatine transporter defect’, Clinical Genetics. Wiley/Blackwell (10.1111), 79(3), pp. 264–272.</bibl>
            <idno type="DOI">10.1111/j.1399-0004.2010.01460.x</idno>
          </bibl>
          <bibl n="7804">
            <bibl>van de Kap, J. M., Pouwels, P. J. W., Aarsen, F. K., ten Hoopen, L. W., Knol, D. L., de Klerk, J. B., de Coo, I. F., Huijmans, J. G. M., Jakobs, C., van der Knaap, M. S., Salomons, G. S. and Mancini, G. M. S. (2012) ‘Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect.’, Journal of inherited metabolic disease. Springer, 35(1), pp. 141–9.</bibl>
            <idno type="DOI">10.1007/s10545-011-9345-1</idno>
          </bibl>
          <bibl n="7805">
            <bibl>Vanderklish, P. W. and Edelman, G. M. (2002) ‘Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons.’, Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 99(3), pp. 1639–44</bibl>
            <idno type="DOI">10.1073/pnas.032681099</idno>
          </bibl>
          <bibl n="7806">
            <bibl>Vela, J., Gutierrez, A., Vitorica, J. and Ruano, D. (2003) ‘Rat hippocampal GABAergic molecular markers are differentially affected by ageing.’, Journal of neurochemistry, 85(2), pp. 368–77.</bibl>
            <idno type="DOI">10.1046/j.1471-4159.2003.01681.x</idno>
          </bibl>
          <bibl n="7807">
            <bibl>von Bernhardi, R., Eugen&amp;#237;n-von Bernhardi, L. and Eugen&amp;#237;n, J. (2015) ‘Microglial cell dysregulation in brain aging and neurodegeneration’, Frontiers in Aging Neuroscience, 7, p. 124.</bibl>
            <idno type="DOI">10.3389/fnagi.2015.00124</idno>
          </bibl>
          <bibl n="7808">
            <bibl>Walker, J. B. (1979) ‘Creatine: biosynthesis, regulation, and function.’, Advances in enzymology and related areas of molecular biology, 50, pp. 177–242.</bibl>
            <idno type="DOI">10.1002/9780470122952.ch4</idno>
          </bibl>
          <bibl n="7809">Wang, H.-S. and Kuo, M.-F. (2007) ‘Vitamin B6 related epilepsy during childhood.’, Chang Gung medical journal, 30(5), pp. 396–401.</bibl>
          <bibl n="7810">
            <bibl>Woo, J. A., Zhao, X., Khan, H., Penn, C., Wang, X., Joly-Amado, A., Weeber, E., Morgan, D. and Kang, D. E. (2015) ‘Slingshot-Cofilin activation mediates mitochondrial and synaptic dysfunction via Aβ ligation to β1-integrin conformers’, Cell Death &amp;amp; Differentiation, 22(6), pp. 921–934.</bibl>
            <idno type="DOI">10.1038/cdd.2015.5</idno>
          </bibl>
          <bibl n="7811">
            <bibl>Wyss, M. and Kaddurah-Daouk, R. (2000) ‘Creatine and Creatinine Metabolism’, Physiological reviews, 80(3), pp. 1107–1213.</bibl>
            <idno type="DOI">10.1016/S1286-0115(06)74505-2</idno>
          </bibl>
          <bibl n="7812">
            <bibl>Xu, D., Zhu, J., Jeong, S., Li, D., Hua, X., Huang, L., Zhang, J., Luo, Y. and Xia, Q. (2018) ‘Rictor Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Suppressing Autophagy and Regulating MAPK Signaling’, Cellular Physiology and Biochemistry, 45(6), pp. 2199–2212.</bibl>
            <idno type="DOI">10.1159/000488165</idno>
          </bibl>
          <bibl n="7813">
            <bibl>Yizhar, O., Fenno, L. E., Prigge, M., Schneider, F., Davidson, T. J., O’Shea, D. J., Sohal, V. S., Goshen, I., Finkelstein, J., Paz, J. T., Stehfest, K., Fudim, R., Ramakrishnan, C., Huguenard, J. R., Hegemann, P. and Deisseroth, K. (2011) ‘Neocortical excitation/inhibition balance in information processing and social dysfunction’, Nature. Nature Publishing Group, 477(7363), pp. 171–178.</bibl>
            <idno type="DOI">10.1038/nature10360</idno>
          </bibl>
          <bibl n="7814">Zervou, S., Whittington, H. J., Russell, A. J. and Lygate, C. A. (2016) ‘Augmentation of Creatine in the Heart.’, Mini reviews in medicinal chemistry, 16(1), pp. 19–28.</bibl>
          <bibl n="7815">
            <bibl>Zhu, X., Lee, H., Raina, A. K., Perry, G. and Smith, M. A. (2002) ‘The Role of Mitogen-Activated Protein Kinase Pathways in Alzheimer’s Disease’, Neurosignals, 11(5), pp. 270–281.</bibl>
            <idno type="DOI">10.1159/000067426</idno>
          </bibl>
        </listBibl>
      </div>
    </body>
  </text>
</TEI>