Abstract
AbstractBipolar-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.
Highlights
Bipolar-disorder is a multifactorial and polygenic psychiatric-illness characterized by switches between depressive and manic mood
We performed a DNA-microarray study searching for pathways commonly affected by chronic lithium treatment and by the knockout of each of the genes
Since IMPA1 KO and SMIT1 KO mice were generated on different backgrounds the microarray analysis was carried out separately for each colony
Summary
Bipolar-disorder is a multifactorial and polygenic psychiatric-illness characterized by switches between depressive and manic mood. Among hypotheses of Li's mechanism the inositol-depletion hypothesis proposes that Li acts by depletion of brain myo-inositol[1]. This is based on the uncompetitive inhibition of inositol monophosphatase-1 (IMPase-1), a key enzyme in the phosphatidylinositol (PI) cycle, by therapeutically-relevant Li levels resulting in decreased myo-inositol (inositol) and subsequent down-regulation of the PI-cycle[2]. Williams et al.[5] demonstrated that the three mood-stabilizers inhibit the collapse of sensory neurons growth cones. This effect was reversed by addition of myo-inositol but not scyllo- or epiinositol[6]
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