SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior

Shaldubina, Alona; Johanson, Roy A.; O’Brien, William T.; Buccafusca, Roberto; Agam, Galila; Belmaker, Robert H.; Klein, Peter S.; Bersudsky, Yuly; Berry, Gerard T.

doi:10.1016/j.ymgme.2006.03.007

Cited by 33 publications

(37 citation statements)

References 25 publications

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“…Consistent with results reported previously for time points between 10 and 35 days (Bersudsky et al, 2007;Cryns et al, 2006;Gould et al, 2007a;O'Brien et al, 2004;Shaldubina et al, 2006), in our experiments 10 days of lithium administration resulted in decreased immobility time in the mouse FST (t(14) = 7.98, p < 0.001; Figure 2a). We have previously reported that i.p.…”

Section: Experiments 2: Time Course For Antidepressant-like Effects Ofsupporting

confidence: 92%

“…administration to rats (Eroglu and Hizal, 1987), acute i.p. administration to mice , and in mice following long-term administration in the chow (Bersudsky et al, 2007;Cryns et al, 2006;Gould et al, 2007a;O'Brien et al, 2004;Shaldubina et al, 2006). To the best of our knowledge, our report is the first to show that lithium by itself has antidepressant-like effects in the TST.…”

Section: Discussionsupporting

confidence: 49%

“…However, limited data exist to suggest that the behavioral effects of lithium in rodent models of mood disorders may be linked to any actions of lithium on AMPA receptor function. Multiple groups have recently shown that long-term administration of lithium in rodent chow results in robust antidepressant-like effects in the FST (Bersudsky et al, 2007;Cryns et al, 2006;Gould et al, 2007a;O'Brien et al, 2004;Shaldubina et al, 2006). The tail suspension test, another measure of antidepressant efficacy, was established in 1985 by Steru and colleagues (Steru et al, 1985), but limited evidence exists for the effects of lithium on this behavioral model.…”

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confidence: 99%

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Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

et al. 2008

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In addition to its clinical antimanic effects, lithium also has efficacy in the treatment of depression. However, the mechanism by which lithium exerts its antidepressant effects is unclear. Our objective was to further characterize the effects of peripheral and central administration of lithium in mouse models of antidepressant efficacy as well as to investigate the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in these behaviors. We utilized the mouse forced swim test (FST) and tail suspension test (TST), intracerebroventricular (ICV) lithium administration, AMPA receptor inhibitors, and BS3 crosslinking followed by western blot. Both short-and long-term administration of lithium resulted in robust antidepressant-like effects in the mouse FST and TST. Using ICV administration of lithium, we show that these effects are due to actions of lithium on the brain, rather than to peripheral effects of the drug. Both ICV and rodent chow (0.4% LiCl) administration paradigms resulted in brain lithium concentrations within the human therapeutic range. The effects of lithium to decrease immobility in the FST and TST were blocked by administration of AMPA receptor inhibitors. Additionally, administration of lithium increased the cell surface expression of GluR1 and GluR2 in the mouse hippocampus. Collectively, these data show that lithium exerts centrally mediated antidepressant-like effects in the mouse FST and TST that require AMPA receptor activation. Lithium may exert its antidepressant effects in humans through AMPA receptors, thus further supporting a role of targeting AMPA receptors as a therapeutic approach for the treatment of depression. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Depression is a severe neuropsychiatric disorder that manifests both as a component of bipolar disorder and unipolar depressive disorder. Bipolar disorder affects at least 1% of the world's population when a strict definition (DSM IV bipolar I disorder) is applied. Major depression is more common than bipolar disorder in the overall population (~ 15% lifetime risk as defined by DSM IV) (Kessler et al., 2005;Sullivan et al., 2000). The recognition of the significant morbidity and mortality (suicide rate of 15%) associated with these severe mood disorders (Evans et al., 2005;Jamison, 2000;Kupfer, 2005), as well as the growing appreciation that a significant percentage of patients either do not respond fully to existing treatments or are intolerant of undesirable side effects, has made the challenge of discovering improved therapeutic agents increasing...

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Section: Experiments 2: Time Course For Antidepressant-like Effects Ofsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 49%

mentioning

confidence: 99%

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Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

et al. 2008

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“…Actually, inositol depletion as a result of dietary inositol restriction (Shaldubina et al, 2006b) or hyponatremia (Bersudsky et al, 1994) has been shown not to sensitize pilocarpine-induced seizures. Along the same line, we recently reported that SMIT heterozygote knockout mice showed reduction in brain inositol levels by about 15-20%, but did not show increased pilocarpine sensitivity (Shaldubina et al, 2006a). SMIT in brain seems to be limited to glia cells (Di Daniel et al, 2006), and it may well be that most of the inositol measured in whole brain is glial inositol.…”

Section: Discussionmentioning

confidence: 80%

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

Cryns¹,

Shamir

Acker

et al. 2007

Neuropsychopharmacol

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Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1 À/À ) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1 À/À mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1 À/À mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1 À/À mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1 À/À mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

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“…administration of lithium. Others have shown more recently that long-term administration of lithium in mouse feed also decreases immobility time (O'Brien et al, 2004;Shaldubina et al, 2006;Bersudsky et al, 2007;Cryns et al, 2007;Gould et al, 2007). The effect of lithium is dependent upon the level of lithium in the blood, and not upon lithium-induced weight loss .…”

Section: Effect Of Lithium On the Forced Swim Testmentioning

confidence: 98%

The behavioral actions of lithium in rodent models: Leads to develop novel therapeutics

O’Donnell

Gould

2007

Neuroscience & Biobehavioral Reviews

121

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For nearly as long as lithium has been in clinical use for the treatment of bipolar disorder, depression, and other conditions, investigators have attempted to characterize its effects on behaviors in rodents. Lithium consistently decreases exploratory activity, rearing, aggression, and amphetamine-induced hyperlocomotion; and it increases the sensitivity to pilocarpine-induced seizures, decreases immobility time in the forced swim test, and attenuates reserpine-induced hypolocomotion. Lithium also predictably induces conditioned taste aversion and alterations in circadian rhythms. The modulation of stereotypy, sensitization, and reward behavior are less consistent actions of the drug. These behavioral models may be relevant to human symptoms and to clinical endophenotypes. It is likely that the actions of lithium in a subset of these animal models are related to the therapeutic efficacy, as well the side effects, of the drug. We conclude with a brief discussion of various molecular mechanisms by which these lithium-sensitive behaviors may be mediated, and comment on the ways in which rat and mouse models can be used more effectively in the future to address persistent questions about the therapeutically relevant molecular actions of lithium.

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SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior

Cited by 33 publications

References 25 publications

Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

The behavioral actions of lithium in rodent models: Leads to develop novel therapeutics

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