Loss of Murine Na+/myo-Inositol Cotransporter Leads to Brain myo-Inositol Depletion and Central Apnea

Berry, Gerard T.; Wu, Shuang; Buccafusca, Roberto; Ren, Jun; Gonzales, Linda W.; Ballard, Philip L.; Golden, Jeffrey A.; Stevens, Martin J.; Greer, John J.

doi:10.1074/jbc.m213176200

Cited by 81 publications

(69 citation statements)

References 49 publications

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“…23 The mouse SMIT gene has been disrupted, but is lethal, causing death just after birth. 30 These mice show an approximately 90% reduction in myo-inositol in the fetal brain, consistent with inhibition of SMIT leading to inositol-depletion. SMIT À/À mice however show no significant loss of PdtIns, 31 arguing that inhibition of SMIT may not be a significant contributor to attenuation of InsP signaling.…”

Section: Inositol Uptake and Mood Stabilizersmentioning

confidence: 56%

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

2004

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Inositol, a simple six-carbon sugar, forms the basis of a number of important intracellular signaling molecules. Over the last 35 years, a series of biochemical and cell biological experiments have shown that lithium (Li þ ) reduces the cellular concentration of myo-inositol and as a consequence attenuates signaling within the cell. Based on these observations, inositol-depletion was proposed as a therapeutic mechanism in the treatment of bipolar mood disorder. Recent results have added significant new dimensions to the original hypothesis. However, despite a number of clinical studies, this hypothesis still remains to be either proven or refuted. In this review of our current knowledge, I will consider where the inositol-depletion hypothesis stands today and how it may be further investigated in the future.

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Section: Inositol Uptake and Mood Stabilizersmentioning

confidence: 56%

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

2004

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“…Animals were maintained on a 12-h/12-h light/dark cycle (lights on between 0800 and 1200 h) with ad libitum access to food and water. All tests were performed during the light phase of the cycle between 0900 and 1900 h. SMIT1 and IMPA1 KO mice were originally generated as previously described (Berry et al, 2003;Cryns et al, 2008). Each KO strain is maintained in a separate colony in our animal-care facility by breeding heterozygote males and females.…”

Section: Animalsmentioning

confidence: 99%

Inositol-Related Gene Knockouts Mimic Lithium’s Effect on Mitochondrial Function

Toker

Bersudsky

Plaschkes

et al. 2013

Neuropsychopharmacol

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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 lithiumtreated 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.

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“…Although neither ITR1 nor INO1 was required for virulence in a mouse model of systemic candidiasis, it was possible that each might compensate for the loss of the other during infection since it has been shown previously that rat serum contains 20 to 100 M inositol (14, 34) and mouse liver contains approximately 100 M inositol (2). In order to test this hypothesis, an attempt was made to disrupt both genes simultaneously.…”

Section: Vol 76 2008 Mechanisms By Which Candida Albicans Acquires mentioning

confidence: 99%

Candida albicans Uses Multiple Mechanisms To Acquire the Essential Metabolite Inositol during Infection

2008

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Candida albicans is an important cause of life-threatening systemic bloodstream infections in immunocompromised patients. In order to cause infections, C. albicans must be able to synthesize the essential metabolite inositol or acquire it from the host. Based on the similarity of C. albicans to Saccharomyces cerevisiae, it was predicted that C. albicans may generate inositol de novo, import it from the environment, or both. The C. albicans inositol synthesis gene INO1 (orf19.7585) and inositol transporter gene ITR1 (orf19.3526) were each disrupted. The ino1⌬/ino1⌬ mutant was an inositol auxotroph, and the itr1⌬/itr1⌬ mutant was unable to import inositol from the medium. Each of these mutants was fully virulent in a mouse model of systemic infection. It was not possible to generate an ino1⌬/ino1⌬ itr1⌬/itr1⌬ double mutant, suggesting that in the absence of these two genes, C. albicans could not acquire inositol and was nonviable. A conditional double mutant was created by replacing the remaining wild-type allele of ITR1 in an ino1⌬/ino1⌬ itr1⌬/ITR1 strain with a conditionally expressed allele of ITR1 driven by the repressible MET3 promoter. The resulting ino1⌬/ ino1⌬ itr1⌬/P MET3 ::ITR1 strain was found to be nonviable in medium containing methionine and cysteine (which represses the P MET3 promoter), and it was avirulent in the mouse model of systemic candidiasis. These results suggest a model in which C. albicans has two equally effective mechanisms for obtaining inositol while in the host. It can either generate inositol de novo through Ino1p, or it can import it from the host through Itr1p.

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Loss of Murine Na+/myo-Inositol Cotransporter Leads to Brain myo-Inositol Depletion and Central Apnea

Cited by 81 publications

References 49 publications

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

Inositol-Related Gene Knockouts Mimic Lithium’s Effect on Mitochondrial Function

Candida albicans Uses Multiple Mechanisms To Acquire the Essential Metabolite Inositol during Infection

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