The inositol depletion hypothesis is not sufficient to explain the behavioral effect of lithium in murine brain

Abstract

A decrease in phosphoinositide synthesis secondary to a decrease in myo-inositol (Ins) levels is central to the inositol depletion hypothesis and has been used to explain the behavioral effects of lithium. In mice, lithium reduces brain Ins content and causes a marked decrease in the time of immobility in the forced swim test (FST). A murine Ins transporter (SMIT1 or SLC5A3) knock-out model developed in our laboratory in which adult SMIT1 (+/−) carrier mice manifest reduced SMIT1 mRNA levels in brain tissue has provided a unique opportunity to test whether the effect of lithium in the FST is mediated by reduced Ins levels. Carrier (+/−) and wild type (+/+) mice with and without lithium treatment were subjected to the FST and then sacrificed for determinations of brain Ins content by GC/MS. The untreated (+/+) and the carriers were immobile for mean times of 92 ± 15 sec (n = 12) and 93 ± 15 sec (n = 12), respectively, while the lithium treated (+/+) mice were immobile for 25 ± 8 sec (n = 12, p = 0.001). The mean hippocampal Ins levels were 7.3 ± 0.2 (n = 6), 5.4 ± 0.6 (n = 6), and 4.9 ± 0.4 (n = 6) mmoles/ kg wet wt. for the (+/+), (+/+) with lithium treatment, and (+/−) mice, respectively. Compared to (+/+) mice, the mean Ins level was decreased by 25% in (+/+) plus lithium (p < 0.05) and by 33% in (+/−) mice (p < 0.05). The absence of a behavioral effect in carriers with Ins deficiency indicates that Ins deficiency is not sufficient to explain the effect of lithium on brain function.