Lithium and fluoxetine regulate the rate of phosphoinositide synthesis in neurons: a new view of their mechanisms of action in bipolar disorder

Abstract

Lithium is widely used to treat bipolar disorder, but its primary mechanism of action is uncertain. One proposal has been that lithium’s ability to inhibit the enzyme inositol monophosphatase (IMPase) reduces the supply of recycled inositol used for membrane phosphoinositide (PIns) synthesis. This 28-year-old hypothesis is still widely debated, however, largely because total levels of PIns in brain or in cultured neurons do not decrease after lithium treatment. Here we use mature cultured cortical neurons to show that, although lithium has little effect on steady-state levels of either inositol or PIns, it markedly inhibits the rate of PIns synthesis. Moreover, we show that rapid synthesis of membrane PIns preferentially uses inositol newly imported from the extracellular space. Unexpectedly, we also find that the antidepressant drug fluoxetine (FLUO: Prozac) stimulates the rate of PIns synthesis. The convergence of both lithium and FLUO in regulating the rate of synthesis of PIns in opposite ways highlights PIns turnover in neurons as a potential new drug target, as well as for understanding mood control in BD. Our results also indicate new avenues for investigation of how neurons regulate their supply of inositol.

Modulation of Oxidative Stress: Pharmaceutical and Pharmacological Aspects 2018

“…This reduces the oxidative stress in the hippocampus [5]. This adds another mechanism to the previously described ability of lithium to inhibit inositol monophosphatase and glycogen synthase kinase-3 [6, 7].…”

Mitochondria under the spotlight: On the implications of mitochondrial dysfunction and its connectivity to neuropsychiatric disorders

“…Studies propose that inositol monophosphatase, an enzyme of the phosphatidylinositol cycle, is inhibited by lithium, leading to reduced myoinositol levels and impeding PKC activation, which is involved in the regulation of neuronal processes affected in BD such as neuronal excitability, neurotransmitter release and neuroplasticity [44] , [45] , [46] ( Fig. 1 C).…”

Crosstalk between Ras and inositol phosphate signaling revealed by lithium action on inositol monophosphatase in Schizophyllum commune

“…However, the increase in higher inositol phosphate species could not be observed using mammalian, plant, or yeasts experimental models (neither with the ascomycete yeasts S. cerevisiae or Schizosaccharomyces pombe, nor the basidiomycetous yeast form of C. neoformans; Lev et al, 2015). Rather, in these organisms the inhibition of IMPase by lithium showed an accumulation of IP 1 , and sometimes of inositol bisphosphate (IP 2 ; Saiardi and Mudge, 2018; Sherman et al, 1981).…”

“…The most polar inositol phosphates (IPs) species, the inositol pyrophosphates IP7 and IP8, are able to regulate basic metabolism (Szijgyarto et al, 2011) thanks to their ability to control phosphate homeostasis (Lonetti et al, 2011; Saiardi, 2012; Wild et al, 2016; Azevedo and Saiardi, 2017). In mammals, inositol signaling regulates neuronal development (Zhang et al, 2017) and affects the physiology of important illnesses such as bipolar disorder (Saiardi and Mudge, 2018) and Alzheimer diseases (Crocco et al, 2016). In plants, inositol signaling is important for drought or salt resistance (Li et al, 2017; Pan et al, 2017), response to phytopathogen attack (Gupta et al, 2017), or mycorrhization (Nanjareddy et al, 2017).…”