title: Phosphoinositide deficiency due to inositol depletion is not a mechanism of lithium action in brain.
abstract: The "inositol depletion hypothesis" has been widely held to be the explanation for both the effect of lithium on brain function, apropos of its use in mood disorders, and on the impairment of development and induction of embryonic malformations in diverse organisms. The essence of the hypothesis is that a deficiency in cellular myo-inositol (Ins), secondary to lithium inhibition of inositol monophosphatase and/or multiple inositol polyphosphate phosphatase activities with trapping of Ins as inositol phosphates, leads to a depression of phosphatidylinositol (PtdIns) and a secondary impairment in inositide signaling. However, the ability of relatively low micromolar levels of Ins to reduce mammalian PtdIns synthetase activity in vivo has never been adequately tested. We have generated a lethal murine brain Ins deficiency model and measured PtdIns content using a novel MALDI-TOF MS method. Our results show that in the most severe Ins deficiency ever recorded in a mammal, the brain PtdIns levels do not decrease. We conclude that PtdIns deficiency due to "inositol depletion" is not a mechanism of lithium action in brain, and that Ins plays another unidentified role in the mammalian brain.
authors.affiliation: Children's Research Institute, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA. gerard.berry@jefferson.edu
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
authors.forename: Roberto
authors.initials: R
authors.lastname: Buccafusca
authors.forename: John J
authors.initials: JJ
authors.lastname: Greer
authors.forename: Eric
authors.initials: E
authors.lastname: Eccleston
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007294:Inositol / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D019964:Mood Disorders / Q000235:genetics / Q000378:metabolism; D010716:Phosphatidylinositols / Q000032:analysis / Q000172:deficiency* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D027981:Symporters / Q000235:genetics; D014020:Tissue Extracts / Q000032:analysis; D000099209:Sodium-Iodide Symporters
chemical_list: D007294:Inositol; D008094:Lithium; D010716:Phosphatidylinositols; D027981:Symporters; D014020:Tissue Extracts; D000099209:Sodium-Iodide Symporters