*Phenotype of mice deficient for SMIT1*

Myoinositol is a precursor of the main inositol-containing phospholipids phosphatidylinositol and phosphatidylinositol-4,5-bisphosphate, a key molecule in cellular signal transduction. In addition, myoinositol has an important role in osmoregulation. The highest myoinositol levels are found in certain regions of the brain with cerebrospinal fluid levels ranging from 2-25 mM, which are higher than levels in the blood.

One hypothesis as to why lithium is effective in the treatment of bipolar disorders is based on its effect on reducing cellular concentrations of myoinositol (the inositol depletion model). Ablation of the murine *SLC5A3* gene demonstrated the significant role of this transporter in maintaining central myoinositol concentrations. SMIT1 knockout mice have significantly reduced central inositol levels with no changes in phosphatidylinositol concentrations. Besides the severe myoinositol deficiency in the brain, those animals display congenital central apnea due to abnormal respiratory rhythmogenesis leading to death shortly after birth. The neonatal lethality of SMIT1 knockout animals appears to be caused by failures in development of peripheral nerves, specifically in nerves controlling breathing. The peripheral nerve abnor‐ malities can be corrected by prenatal myoinositol supplementation suggesting that myoino‐ sitol is required for peripheral nerve development. Phenotypic analysis of homozygous SMIT1 knockout mice indicated, that a reduction of central inositol levels is associated with lithiumlike neurobehavioral effects. Potentially, the inositol depletion hypothesis as a mode of action for lithium might be supported by the phenotypic characteristics of SMIT1 knockout mice [21].
