Knockout mice in understanding the mechanism of action of lithium

Abstract

Lithium inhibits IMPase (inositol monophosphatase) activity, as well as inositol transporter function. To determine whether one or more of these mechanisms might underlie lithium's behavioural effects, we studied Impa1 (encoding IMPase) and Smit1 (sodium-myo-inositol transporter 1)-knockout mice. In brains of adult homozygous Impa1-knockout mice, IMPase activity was found to be decreased; however, inositol levels were not found to be altered. Behavioural analysis indicated decreased immobility in the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures. These are behaviours robustly induced by lithium. In homozygous Smit1-knockout mice, free inositol levels were decreased in the frontal cortex and hippocampus. These animals behave like lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced-swim test model of depression. In contrast with O'Brien et al. [O'Brien, Harper, Jove, Woodgett, Maretto, Piccolo and Klein (2004) J. Neurosci. 24, 6791-6798], we could not confirm that heterozygous Gsk3b (glycogen synthase kinase 3beta)-knockout mice exhibit decreased immobility in the Porsolt forced-swim test or decreased amphetamine-induced hyperactivity in a manner mimicking lithium's behavioural effects. These data support the role of inositol-related processes rather than GSK3beta in the mechanism of the therapeutic action of lithium.

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

“…We were able to evaluate inositol-mediated gene expression changes because of our simultaneous analysis of expression changes in Li-treated mice and in mice harboring KO of either IMPA1 or Slc5a3, both encoding proteins related to the PI cycle and shown to be affected by therapeutic levels of the drug. Our group has previously reported Li-like behavioral and neurochemical phenotypes exhibited by these two strains of KO mice (Agam et al, 2009). …”

“…Both of these genes encode for proteins known to be affected by chronic Li treatment (inositol monophosphatase1 designated as IMPase1 and sodium-myo-inositol transporter designated as SMIT1) (Hallcher and Sherman, 1980;Lubrich and van Calker, 1999). These KO mice share several mood stabilization-related behavioral and neurochemical characteristics with lithium treatment, favoring the notion that inositol metabolism is involved in the mechanism of Li-induced behavioral changes (Agam et al, 2009). Thus, they seemed to provide an opportunity to examine which of the many reported effects of lithium on gene expression could potentially be involved in Li-induced behavioral effects, specifically those mediated by the drug's effect on inositol metabolism.…”

“…In an attempt to provide evidence for the inositoldepletion hypothesis, we have studied two strains of KO mice with deletion of genes involved in PI signal transduction, IMPA1 and Slc5a3 (Agam et al, 2009). Both of these genes encode for proteins known to be affected by chronic Li treatment (inositol monophosphatase1 designated as IMPase1 and sodium-myo-inositol transporter designated as SMIT1) (Hallcher and Sherman, 1980;Lubrich and van Calker, 1999).…”

Is prenatal myo‐inositol deficiency a mechanism of CNS injury in galactosemia?

“…However, administration of pharmacologic amounts of myo-inositol via the drinking water of the pregnant female carrier mouse before E9.5 will rescue the lethal phenotype 100% of the time (Buccafusca et al 2008;Chau et al 2005). The knockout mice require no myo-inositol treatment beyond the weaning period to survive, but as adults with myo-inositol deficiency they manifest abnormal brain behavioral tests which mimic those seen in rodents exposed to lithium, a drug used to treat mood disorders (Buccafusca et al 2008;Agam et al 2009). In summary, we have created a unique mammalian model of fetal myo-inositol deficiency so severe that it recapitulates the 90% degree of brain myoinositol deficiency detected in the infant with galactosemia in the post-mortem state.…”

Lithium: Sixty Years Thereafter

“…It should also be mentioned that Robert Belmaker has been a reputable researcher of the lithium mechanism of action and, especially, the connection of the lithium therapeutic effect in bipolar disorder with a phosphatidylinositol (PI) system. Convincing evidence for such an effect was provided in a recent work of his group on Impa1 and Smit1 knockout mice [11] . This may concur with the results of one of the recent genome-wide association studies of bipolar disorder where the strongest association signal among over 550,000 single nucleotide polymorphisms was detected at a marker connected with the PI pathway [12] .…”