Monoamine oxidase A and A/B knockout mice display autistic-like features
Identifieur interne : 002304 ( Main/Curation ); précédent : 002303; suivant : 002305Monoamine oxidase A and A/B knockout mice display autistic-like features
Auteurs : Marco Bortolato [États-Unis] ; Sean C. Godar [États-Unis] ; Loai Alzghoul [États-Unis] ; Junlin Zhang [États-Unis] ; Ryan D. Darling [États-Unis] ; Kimberly L. Simpson [États-Unis] ; Valentina Bini [Italie] ; Kevin Chen [États-Unis] ; Cara L. Wellman [États-Unis] ; Rick C. S. Lin [États-Unis] ; Jean C. Shih [États-Unis]Source :
- The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) [ 1461-1457 ] ; 2012.
Abstract
Converging lines of evidence show that a sizable subset of autism-spectrum disorders (ASDs) is characterized by increased blood levels of serotonin (5-hydroxytryptamine, 5-HT), yet the mechanistic link between these two phenomena remains unclear. The enzymatic degradation of brain 5-HT is mainly mediated by monoamine oxidase (MAO)A and, in the absence of this enzyme, by its cognate isoenzyme MAOB. MAOA and A/B knockout (KO) mice display high 5-HT levels, particularly during early developmental stages. Here we show that both mutant lines exhibit numerous behavioural hallmarks of ASDs, such as social and communication impairments, perseverative and stereotypical responses, behavioural inflexibility, as well as subtle tactile and motor deficits. Furthermore, both MAOA and A/B KO mice displayed neuropathological alterations reminiscent of typical ASD features, including reduced thickness of the corpus callosum, increased dendritic arborization of pyramidal neurons in the prefrontal cortex and disrupted microarchitecture of the cerebellum. The severity of repetitive responses and neuropathological aberrances was generally greater in MAOA/B KO animals. These findings suggest that the neurochemical imbalances induced by MAOAdeficiency (either by itself or in conjunction with lack of MAOB) may result in an array of abnormalities similar to those observed in ASDs. Thus, MAOA and A/B KO mice may afford valuable models to help elucidate the neurobiological bases of these disorders and related neurodevelopmental problems.
Url:
DOI: 10.1017/S1461145712000715
PubMed: 22850464
PubMed Central: 3517692
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Godar</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName><orgName type="university">Université de Californie du Sud</orgName></affiliation></author><author><name sortKey="Alzghoul, Loai" sort="Alzghoul, Loai" uniqKey="Alzghoul L" first="Loai" last="Alzghoul">Loai Alzghoul</name><affiliation wicri:level="2"><nlm:aff id="A2">Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS</wicri:regionArea><placeName><region type="state">État du Mississippi</region></placeName></affiliation></author><author><name sortKey="Zhang, Junlin" sort="Zhang, Junlin" uniqKey="Zhang J" first="Junlin" last="Zhang">Junlin Zhang</name><affiliation wicri:level="2"><nlm:aff id="A3">Department of Surgery, University of Mississippi Medical Center, Jackson, MS, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Surgery, University of Mississippi Medical Center, Jackson, MS</wicri:regionArea><placeName><region type="state">État du Mississippi</region></placeName></affiliation></author><author><name sortKey="Darling, Ryan D" sort="Darling, Ryan D" uniqKey="Darling R" first="Ryan D." last="Darling">Ryan D. Darling</name><affiliation wicri:level="2"><nlm:aff id="A4">Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS</wicri:regionArea><placeName><region type="state">État du Mississippi</region></placeName></affiliation></author><author><name sortKey="Simpson, Kimberly L" sort="Simpson, Kimberly L" uniqKey="Simpson K" first="Kimberly L." last="Simpson">Kimberly L. Simpson</name><affiliation wicri:level="2"><nlm:aff id="A4">Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS</wicri:regionArea><placeName><region type="state">État du Mississippi</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A5">Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS</wicri:regionArea><placeName><region type="state">État du Mississippi</region></placeName></affiliation></author><author><name sortKey="Bini, Valentina" sort="Bini, Valentina" uniqKey="Bini V" first="Valentina" last="Bini">Valentina Bini</name><affiliation wicri:level="1"><nlm:aff id="A6">Guy Everett’ Laboratory Department of Neuroscience ‘B. B. Brodie’, University of Cagliari, Monserrato, CA, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Guy Everett’ Laboratory Department of Neuroscience ‘B. B. Brodie’, University of Cagliari, Monserrato, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Kevin" sort="Chen, Kevin" uniqKey="Chen K" first="Kevin" last="Chen">Kevin Chen</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName><orgName type="university">Université de Californie du Sud</orgName></affiliation></author><author><name sortKey="Wellman, Cara L" sort="Wellman, Cara L" uniqKey="Wellman C" first="Cara L." last="Wellman">Cara L. Wellman</name><affiliation wicri:level="2"><nlm:aff id="A7">Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, IN, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, IN</wicri:regionArea><placeName><region type="state">Indiana</region></placeName></affiliation></author><author><name sortKey="Lin, Rick C S" sort="Lin, Rick C S" uniqKey="Lin R" first="Rick C. S." last="Lin">Rick C. S. Lin</name><affiliation wicri:level="2"><nlm:aff id="A4">Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS</wicri:regionArea><placeName><region type="state">État du Mississippi</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A5">Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS</wicri:regionArea><placeName><region type="state">État du Mississippi</region></placeName></affiliation></author><author><name sortKey="Shih, Jean C" sort="Shih, Jean C" uniqKey="Shih J" first="Jean C." last="Shih">Jean C. Shih</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName><orgName type="university">Université de Californie du Sud</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="A8">Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName><orgName type="university">Université de Californie du Sud</orgName></affiliation></author></analytic><series><title level="j">The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)</title><idno type="ISSN">1461-1457</idno><idno type="eISSN">1469-5111</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Converging lines of evidence show that a sizable subset of autism-spectrum disorders (ASDs) is characterized by increased blood levels of serotonin (5-hydroxytryptamine, 5-HT), yet the mechanistic link between these two phenomena remains unclear. The enzymatic degradation of brain 5-HT is mainly mediated by monoamine oxidase (MAO)A and, in the absence of this enzyme, by its cognate isoenzyme MAOB. MAOA and A/B knockout (KO) mice display high 5-HT levels, particularly during early developmental stages. Here we show that both mutant lines exhibit numerous behavioural hallmarks of ASDs, such as social and communication impairments, perseverative and stereotypical responses, behavioural inflexibility, as well as subtle tactile and motor deficits. Furthermore, both MAOA and A/B KO mice displayed neuropathological alterations reminiscent of typical ASD features, including reduced thickness of the corpus callosum, increased dendritic arborization of pyramidal neurons in the prefrontal cortex and disrupted microarchitecture of the cerebellum. The severity of repetitive responses and neuropathological aberrances was generally greater in MAOA/B KO animals. These findings suggest that the neurochemical imbalances induced by MAOAdeficiency (either by itself or in conjunction with lack of MAOB) may result in an array of abnormalities similar to those observed in ASDs. Thus, MAOA and A/B KO mice may afford valuable models to help elucidate the neurobiological bases of these disorders and related neurodevelopmental problems.</p></div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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