Monoamine oxidase A and A/B knockout mice display autistic-like features
Identifieur interne : 001659 ( Pmc/Checkpoint ); précédent : 001658; suivant : 001660Monoamine 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
Affiliations:
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<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>
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<contrib-group><contrib contrib-type="author"><name><surname>Bortolato</surname>
<given-names>Marco</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref rid="FN2" ref-type="author-notes">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Godar</surname>
<given-names>Sean C.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref rid="FN2" ref-type="author-notes">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alzghoul</surname>
<given-names>Loai</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Junlin</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Darling</surname>
<given-names>Ryan D.</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Simpson</surname>
<given-names>Kimberly L.</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bini</surname>
<given-names>Valentina</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Kevin</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wellman</surname>
<given-names>Cara L.</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lin</surname>
<given-names>Rick C. S.</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shih</surname>
<given-names>Jean C.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A8">8</xref>
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<aff id="A1"><label>1</label>
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA</aff>
<aff id="A2"><label>2</label>
Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, USA</aff>
<aff id="A3"><label>3</label>
Department of Surgery, University of Mississippi Medical Center, Jackson, MS, USA</aff>
<aff id="A4"><label>4</label>
Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA</aff>
<aff id="A5"><label>5</label>
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA</aff>
<aff id="A6"><label>6</label>
Guy Everett’ Laboratory Department of Neuroscience ‘B. B. Brodie’, University of Cagliari, Monserrato, CA, Italy</aff>
<aff id="A7"><label>7</label>
Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, IN, USA</aff>
<aff id="A8"><label>8</label>
Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA</aff>
<author-notes><corresp id="FN1">Address for correspondence: J. C. Shih, Department of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Southern California, PSC 518, 1985 Zonal Ave, Los Angeles, CA 90089, USA., <italic>Tel.</italic>
: 323 442 1441, <italic>Fax</italic>
: 323 442 3229, <email>jcshih@usc.edu</email>
</corresp>
<fn id="FN2" fn-type="equal"><label>*</label>
<p>These authors contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>16</day>
<month>8</month>
<year>2012</year>
</pub-date>
<pub-date pub-type="epub"><day>31</day>
<month>7</month>
<year>2012</year>
</pub-date>
<pub-date pub-type="ppub"><month>5</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>5</month>
<year>2013</year>
</pub-date>
<volume>16</volume>
<issue>4</issue>
<fpage>869</fpage>
<lpage>888</lpage>
<permissions><copyright-statement>© CINP 2012</copyright-statement>
<copyright-year>2012</copyright-year>
</permissions>
<abstract><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>
</abstract>
<kwd-group><kwd>Animal models</kwd>
<kwd>autistic-spectrum disorders</kwd>
<kwd>monoamine oxidase</kwd>
</kwd-group>
<funding-group><award-group><funding-source country="United States">National Institute of Mental Health : NIMH</funding-source>
<award-id>R01 MH039085 || MH</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Italie</li>
<li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Indiana</li>
<li>État du Mississippi</li>
</region>
<orgName><li>Université de Californie du Sud</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Californie"><name sortKey="Bortolato, Marco" sort="Bortolato, Marco" uniqKey="Bortolato M" first="Marco" last="Bortolato">Marco Bortolato</name>
</region>
<name sortKey="Alzghoul, Loai" sort="Alzghoul, Loai" uniqKey="Alzghoul L" first="Loai" last="Alzghoul">Loai Alzghoul</name>
<name sortKey="Chen, Kevin" sort="Chen, Kevin" uniqKey="Chen K" first="Kevin" last="Chen">Kevin Chen</name>
<name sortKey="Darling, Ryan D" sort="Darling, Ryan D" uniqKey="Darling R" first="Ryan D." last="Darling">Ryan D. Darling</name>
<name sortKey="Godar, Sean C" sort="Godar, Sean C" uniqKey="Godar S" first="Sean C." last="Godar">Sean C. Godar</name>
<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>
<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>
<name sortKey="Shih, Jean C" sort="Shih, Jean C" uniqKey="Shih J" first="Jean C." last="Shih">Jean C. Shih</name>
<name sortKey="Shih, Jean C" sort="Shih, Jean C" uniqKey="Shih J" first="Jean C." last="Shih">Jean C. Shih</name>
<name sortKey="Simpson, Kimberly L" sort="Simpson, Kimberly L" uniqKey="Simpson K" first="Kimberly L." last="Simpson">Kimberly L. Simpson</name>
<name sortKey="Simpson, Kimberly L" sort="Simpson, Kimberly L" uniqKey="Simpson K" first="Kimberly L." last="Simpson">Kimberly L. Simpson</name>
<name sortKey="Wellman, Cara L" sort="Wellman, Cara L" uniqKey="Wellman C" first="Cara L." last="Wellman">Cara L. Wellman</name>
<name sortKey="Zhang, Junlin" sort="Zhang, Junlin" uniqKey="Zhang J" first="Junlin" last="Zhang">Junlin Zhang</name>
</country>
<country name="Italie"><noRegion><name sortKey="Bini, Valentina" sort="Bini, Valentina" uniqKey="Bini V" first="Valentina" last="Bini">Valentina Bini</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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