SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior.
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.
Shaldubina
Alona
A
Stanley Research Center, Faculty of Health Sciences, Ben Gurion University of the Negev and Mental Health Center, Beer Sheva, Israel.
Johanson
Roy A
RA
O'Brien
W Timothy
WT
Buccafusca
Roberto
R
Agam
Galila
G
Belmaker
R H
RH
Klein
Peter S
PS
Bersudsky
Yuly
Y
Berry
Gerard T
GT
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*
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