Knockout mice in understanding the mechanism of action of lithium

  • Prof Galila Agam, Ben Gurion University, Israel
  • Dr Yuly Bersudsky, Ben Gurion University, Israel
  • Prof Gerard Berry, Harvard University, United States
  • Prof Diederik Moechars, Johnson & Johnson Pharmaceutical, Belgium
  • Dr Yael Lavi-Avnon, Ben Gurion University, Israel
  • Prof RH Belmaker, Ben Gurion University, Israel

Objectives: Lithium inhibits inositol monophosphatase (IMPase) activity as well as inositol transporter function. To determine if one or more of these mechanisms might underly lithium's behavioral effects we studied IMPA1 gene knockout and inositol transporter (SMIT) gene knockout mice.
Methods and Results: In brains of adult homozygote IMPA1 knockout mice, IMPase activity was found to be reduced. Behavioral analysis indicated reduced immobility in the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures. These are behaviors robustly induced by lithium. In SMIT homozygote knockout mice free inositol levels were reduced 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 to O'Brien et al (2004), we could not confirm that GSK-3beta heterozygote knockout mice exhibit reduced immobility in the Porsolt forced-swim test or reduced amphetamine-induced hyperactivity in a manner mimicking lithium's behavioral effects.
Conclusions: These data support the role of inositol related processes rather than GSK-3beta in the mechanism of the therapeutic action of lithium.