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

Bipolar-disorder, characterized by switches between depressive and manic mood, is treated by mood-stabilizers, lithium being one of them. Among hypotheses suggested, the inositol-depletion hypothesis proposes that lithium attenuates hyperactivation of phosphatidylinositol signaling linked to neurotransmission-related receptors.Available for us are knockout-mice of two genes (IMPA1 or Slc5a3) each encoding for a protein related to inositol metabolism. We previously characterized these mice as exhibiting lithium-like neurochemical and behavioral phenotype. We performed a DNA-microarray study searching for pathways commonly affected by chronic lithium treatment and by the knockout of each of the genes. Here we show up-regulation of mitochondrial function in the three paradigms studied. To verify this result, the interrelationship between treatment with lithium and rotenone, an inhibitor of mitochondrial function, was studied behaviorally. Lithium and rotenone counteracted each other's effects in two bipolar-related models. The results support the inositol-depletion hypothesis and suggest amelioration of aberrant mitochondrial function consequent to inositol-depletion.