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Inositol-related gene knockouts mimic lithium's effect on mitochondrial function.
Toker, Lilach; Bersudsky, Yuly; Plaschkes, Inbar; Chalifa-Caspi, Vered; Berry, Gerard T; Buccafusca, Roberto; Moechars, Dieder; Belmaker, R H; Agam, Galila.
Afiliação
  • Toker L; 1] Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel [2] Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel [3] Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • Bersudsky Y; 1] Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel [2] Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel [3] Mental Health Center, Beer-Sheva, Israel.
  • Plaschkes I; National Institute for Biotechnology in the Negev (NIBN), Beer-Sheva, Israel.
  • Chalifa-Caspi V; National Institute for Biotechnology in the Negev (NIBN), Beer-Sheva, Israel.
  • Berry GT; Metabolism Program Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
  • Buccafusca R; Metabolism Program Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
  • Moechars D; Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium.
  • Belmaker RH; 1] Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel [2] Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel [3] Mental Health Center, Beer-Sheva, Israel.
  • Agam G; 1] Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel [2] Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel [3] Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Neuropsychopharmacology ; 39(2): 319-28, 2014 Jan.
Article em En | MEDLINE | ID: mdl-23924600
The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium's/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria-related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium's effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium's effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Técnicas de Inativação de Genes / Inositol / Lítio / Mitocôndrias Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Técnicas de Inativação de Genes / Inositol / Lítio / Mitocôndrias Idioma: En Ano de publicação: 2014 Tipo de documento: Article