title: SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior.
abstract: Two leading hypotheses to explain lithium action in bipolar disorder propose either inositol depletion or inhibition of GSK-3 as mechanisms of action. Behavioral effects of lithium are mimicked in Gsk-3beta+/- mice, but the contribution of inositol depletion to these behaviors has not been tested. According to the inositol depletion hypothesis, lithium-sensitive behavior is secondary to impaired phosphatidylinositol synthesis caused by inositol deficiency. By disrupting the sodium myo-inositol transporter1 gene, SMIT1, we show that depletion of brain myo-inositol in SMIT1+/- mice has no effect on lithium-sensitive behavior. These findings, taken together with our previous work showing that SMIT-/- mice have an even greater depletion of inositol in brain with no reduction in phosphatidylinositol levels, are difficult to reconcile with the current formulation of the inositol depletion hypothesis.
authors.affiliation: Stanley Research Center, Faculty of Health Sciences, Ben Gurion University of the Negev and Mental Health Center, Beer Sheva, Israel.
authors.forename: Alona
authors.initials: A
authors.lastname: Shaldubina
authors.forename: Roy A
authors.initials: RA
authors.lastname: Johanson
authors.forename: W Timothy
authors.initials: WT
authors.lastname: O'Brien
authors.forename: Roberto
authors.initials: R
authors.lastname: Buccafusca
authors.forename: Galila
authors.initials: G
authors.lastname: Agam
authors.forename: R H
authors.initials: RH
authors.lastname: Belmaker
authors.forename: Peter S
authors.initials: PS
authors.lastname: Klein
authors.forename: Yuly
authors.initials: Y
authors.lastname: Bersudsky
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D001921:Brain / Q000378:metabolism*; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007294:Inositol / Q000172:deficiency / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D027981:Symporters / Q000235:genetics*
chemical_list: C508355:SLC5A3 protein, mouse; D027981:Symporters; D007294:Inositol; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3