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

Translational Psychiatry
Adolfo Saiardi, Anne W Mudge

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.

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Citations

Sep 12, 2019·Frontiers in Molecular Neuroscience·Padinjat RaghuSankhanil Saha
Jul 30, 2019·Oxidative Medicine and Cellular Longevity·Robert E SmithLuciano Saso
Jan 9, 2019·Orphanet Journal of Rare Diseases·Christopher P WalkerRaymond Y Cho
Nov 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Yann DesfougèresAdolfo Saiardi
Oct 10, 2020·Computational and Structural Biotechnology Journal·Mara ZilocchiMohan Babu
Nov 16, 2019·International Journal of Biological Macromolecules·Prakarsh K YadavSaurabh C Saxena
Feb 25, 2021·Cell Reports·Catia AndreassiAntonella Riccio

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Methods Mentioned

BETA
electron microscopy

Software Mentioned

FLUO

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