Abstract
Inositol, a simple six-carbon sugar, forms the basis of a number of important intracellular signaling molecules. Over the last 35 years, a series of biochemical and cell biological experiments have shown that lithium (Li+) reduces the cellular concentration of myo-inositol and as a consequence attenuates signaling within the cell. Based on these observations, inositol-depletion was proposed as a therapeutic mechanism in the treatment of bipolar mood disorder. Recent results have added significant new dimensions to the original hypothesis. However, despite a number of clinical studies, this hypothesis still remains to be either proven or refuted. In this review of our current knowledge, I will consider where the inositol-depletion hypothesis stands today and how it may be further investigated in the future.
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References
Berridge MJ, Downes CP, Hanley MR . Neural and developmental actions of lithium: a unifying hypothesis. Cell 1989; 59: 411–419.
Harwood AJ, Agam G . Search for a common mechanism of mood stabilizers. Biochem Pharmacol 2003; 66: 179–189.
Allison JH, Stewart MA . Reduced brain inositol in lithium-treated rats. Nat New Biol 1971; 233: 267–268.
Allison JH, Blisner ME, Holland WH, Hipps PP, Sherman WR . Increased brain myo-inositol 1-phosphate in lithium-treated rats. Biochem Biophys Res Commun 1976; 71: 664–670.
Naccarato WF, Ray RE, Wells WW . Biosynthesis of myo-inositol in rat mammary gland. Isolation and properties of the enzymes. Arch Biochem Biophys 1974; 164: 194–201.
Hallcher LM, Sherman WR . The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J Biol Chem 1980; 255: 10896–10901.
Atack JR, Broughton HB, Pollack SJ . Structure and mechanism of inositol monophosphatase. FEBS Lett 1995; 361: 1–7.
Mikoshiba K . Inositol 1,4,5-trisphosphate receptor. Trends Pharmacol Sci 1993; 14: 86–89.
Shears SB . How versatile are inositol phosphate kinases? Biochem J 2004; 377: 265–280.
Fisher SK, Novak JE, Agranoff BW . Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance. J Neurochem 2002; 82: 736–754.
Inhorn RC, Majerus PW . Inositol polyphosphate 1-phosphatase from calf brain. Purification and inhibition by Li+, Ca2+, and Mn2+. J Biol Chem 1987; 262: 15946–15952.
Emilien G, Maloteaux JM, Seghers A, Charles G . Lithium compared to valproic acid and carbamazepine in the treatment of mania: a statistical meta-analysis. Eur Neuropsychopharmacol 1996; 6: 245–252.
O'Donnell T, Rotzinger S, Nakashima TT, Hanstock CC, Ulrich M, Silverstone PH . Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain. Brain Res 2000; 880: 84–91.
Vaden DL, Ding D, Peterson B, Greenberg ML . Lithium and valproate decrease inositol mass and increase expression of the yeast INO1 and INO2 genes for inositol biosynthesis. J Biol Chem 2001; 276: 15466–15471.
Williams RS, Cheng L, Mudge AW, Harwood AJ . A common mechanism of action for three mood-stabilizing drugs. Nature 2002; 417: 292–295.
Shamir A, Shaltiel G, Greenberg ML, Belmaker RH, Agam G . The effect of lithium on expression of genes for inositol biosynthetic enzymes in mouse hippocampus; a comparison with the yeast model. Brain Res Mol Brain Res 2003; 115: 104–110.
Williams RS, Eames M, Ryves WJ, Viggars J, Harwood AJ . Loss of a prolyl oligopeptidase confers resistance to lithium by elevation of inositol (1,4,5) trisphosphate. EMBO J 1999; 18: 2734–2745.
Shaltiel G, Shamir A, Shapiro J, Ding D, Dalton E, Bialer M et al. Valproate decreases inositol biosynthesis. Biol Psychiatry 2004 (in press).
Schulz I, Gerhartz B, Neubauer A, Holloschi A, Heiser U, Hafner M et al. Modulation of inositol 1,4,5-triphosphate concentration by prolyl endopeptidase inhibition. Eur J Biochem 2002; 269: 5813–5820.
Eickholt BJ, Williams RSB, Harwood AJ . Mood stabilizers and the cell biology of neuronal growth cones. Clin Neurosci Res 2004 (in press).
Emilien G, Maloteaux JM, Seghers A, Charles G . Lithium therapy in the treatment of manic-depressive illness. Present status and future perspectives. A critical review. Arch Int Pharmacodyn Ther 1995; 330: 251–278.
Shaltiel G, Dalton E, Belmaker RH, Harwood AJ, Agam G . Specificity of mood stabilizer action on neuronal growth cones. (ms submitted). 2004.
van Calker D, Belmaker RH . The high affinity inositol transport system—implications for the pathophysiology and treatment of bipolar disorder. Bipolar Disord 2000; 2: 102–107.
Inoue K, Shimada S, Minami Y, Morimura H, Miyai A, Yamauchi A et al. Cellular localization of Na+/MYO-inositol co-transporter mRNA in the rat brain. Neuroreport 1996; 7: 1195–1198.
Lubrich B, Spleiss O, Gebicke-Haerter PJ, van Calker D . Differential expression, activity and regulation of the sodium/myo-inositol cotransporter in astrocyte cultures from different regions of the rat brain. Neuropharmacology 2000; 39: 680–690.
Uldry M, Ibberson M, Horisberger JD, Chatton JY, Riederer BM, Thorens B . Identification of a mammalian H(+)-myo-inositol symporter expressed predominantly in the brain. EMBO J 2001; 20: 4467–4477.
Uldry M, Steiner P, Zurich MG, Beguin P, Hirling H, Dolci W et al. Regulated exocytosis of an H(+)/myo-inositol symporter at synapses and growth cones. EMBO J 2004; 23: 531–540.
Wolfson M, Bersudsky Y, Zinger E, Simkin M, Belmaker RH, Hertz L . Chronic treatment of human astrocytoma cells with lithium, carbamazepine or valproic acid decreases inositol uptake at high inositol concentrations but increases it at low inositol concentrations. Brain Res 2000; 855: 158–161.
Wolfson M, Hertz E, Belmaker RH, Hertz L . Chronic treatment with lithium and pretreatment with excess inositol reduce inositol pool size in astrocytes by different mechanisms. Brain Res 1998; 787: 34–40.
Berry GT, Wu S, Buccafusca R, Ren J, Gonzales LW, Ballard PL et al. Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea. J Biol Chem 2003; 278: 18297–18302.
Berry GT, Buccafusca R, Greer JJ, Eccleston E . Phosphoinositide deficiency due to inositol depletion is not a mechanism of lithium action in brain. Mol Genet Metab 2004; 82: 87–92.
Berry GT, Wang ZJ, Dreha SF, Finucane BM, Zimmerman RA . In vivo brain myo-inositol levels in children with Down syndrome. J Pediatr 1999; 135: 94–97.
Atack JR, Broughton HB, Pollack SJ . Inositol monophosphatase—a putative target for Li+ in the treatment of bipolar disorder. Trends Neurosci 1995; 18: 343–349.
Lopez-Coronado JM, Belles JM, Lesage F, Serrano R, Rodriguez PL . A novel mammalian lithium-sensitive enzyme with a dual enzymatic activity, 3′-phosphoadenosine 5′-phosphate phosphatase and inositol-polyphosphate 1-phosphatase. J Biol Chem 1999; 274: 16034–16039.
Miyamoto R, Sugiura R, Kamitani S, Yada T, Lu Y, Sio SO et al. Tol1, a fission yeast phosphomonoesterase, is an in vivo target of lithium, and its deletion leads to sulfite auxotrophy. J Bacteriol 2000; 182: 3619–3625.
Ray Jr WJ, Post CB, Puvathingal JM . Comparison of rate constants for (PO3−) transfer by the Mg(II), Cd(II), and Li(I) forms of phosphoglucomutase. Biochemistry 1989; 28: 559–569.
Masuda CA, Xavier MA, Mattos KA, Galina A, Montero-Lomeli M . Phosphoglucomutase is an in vivo lithium target in yeast. J Biol Chem 2001; 276: 37794–37801.
Pang H, Koda Y, Soejima M, Kimura H . Identification of human phosphoglucomutase 3 (PGM3) as N-acetylglucosamine-phosphate mutase (AGM1). Ann Hum Genet 2002; 66: 139–144.
Klein PS, Melton DA . A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 1996; 93: 8455–8459.
Woodgett JR . Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J 1990; 9: 2431–2438.
Ryves WJ, Harwood AJ . Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem Biophys Res Commun 2001; 280: 720–725.
Ryves WJ, Dajani R, Pearl L, Harwood AJ . Glycogen synthase kinase-3 inhibition by lithium and beryllium suggests the presence of two magnesium binding sites. Biochem Biophys Res Commun 2002; 290: 967–972.
Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J . Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 2001; 20: 27–39.
King TD, Bijur GN, Jope RS . Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium. Brain Res 2001; 919: 106–114.
Bijur GN, De Sarno P, Jope RS . Glycogen synthase kinase-3beta facilitates staurosporine- and heat shock-induced apoptosis. Protection by lithium. J Biol Chem 2000; 275: 7583–7590.
Takashima A, Noguchi K, Sato K, Hoshino T, Imahori K . Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity. Proc Natl Acad Sci USA 1993; 90: 7789–7793.
Takashima A, Noguchi K, Michel G, Mercken M, Hoshi M, Ishiguro K et al. Exposure of rat hippocampal neurons to amyloid beta peptide (25–35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 beta. Neurosci Lett 1996; 203: 33–36.
Harwood AJ . Signal transduction: Life, the universe and development. Curr Biol 2000; 10: R116–R119.
Pap M, Cooper GM . Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J Biol Chem 1998; 273: 19929–19932.
Bhat RV, Shanley J, Correll MP, Fieles WE, Keith RA, Scott CW et al. Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci USA 2000; 97: 11074–11079.
Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ et al. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol 2000; 7: 793–803.
Eickholt BJ, Walsh FS, Doherty P . An inactive pool of GSK-3 at the leading edge of growth cones is implicated in Semaphorin 3A signaling. J Cell Biol 2002; 157: 211–217.
Nusse R (2004); http://www.stanford.edu/~rnusse/wntwindow.html.
Lucas FR, Goold RG, Gordon-Weeks PR, Salinas PC . Inhibition of GSK-3beta leading to the loss of phosphorylated MAP-1B is an early event in axonal remodelling induced by WNT-7a or lithium. J Cell Sci 1998; 111: 1351–1361.
Ciani L, Krylova O, Smalley MJ, Dale TC, Salinas PC . A divergent canonical WNT-signaling pathway regulates microtubule dynamics: dishevelled signals locally to stabilize microtubules. J Cell Biol 2004; 164: 243–253.
Garrity PA . Developmental biology: how neurons avoid derailment. Nature 2003; 422: 570–571.
He X . Wnt signaling went derailed again: a new track via the LIN-18 receptor? Cell 2004; 118: 668–670.
Lu W, Yamamoto V, Ortega B, Baltimore D . Mammalian ryk is a wnt coreceptor required for stimulation of neurite outgrowth. Cell 2004; 119: 97–108.
O'Brien WT, Harper AD, Jove F, Woodgett JR, Maretto S, Piccolo S et al. Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 2004; 24: 6791–6798.
Gould TD, Einat H, Bhat R, Manji HK . AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. Int J Neuropsychopharmacol 2004; 1–4.
Kaidanovich-Beilin O, Milman A, Weizman A, Pick CG, Eldar-Finkelman H . Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus. Biol Psychiatry 2004; 55: 781–784.
Chen G, Huang LD, Jiang YM, Manji HK . The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem 1999; 72: 1327–1330.
Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS . Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 2001; 276: 36734–36741.
Hall AC, Brennan A, Goold RG, Cleverley K, Lucas FR, Gordon-Weeks PR et al. Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons. Mol Cell Neurosci 2002; 20: 257–270.
De Sarno P, Li X, Jope RS . Regulation of Akt and glycogen synthase kinase-3beta phosphorylation by sodium valproate and lithium. Neuropharmacology 2002; 43: 1158–1164.
Allison JH, Boshans RL, Hallcher LM, Packman PM, Sherman WR . The effects of lithium on myo-inositol levels in layers of frontal cerebral cortex, in cerebellum, and in corpus callosum of the rat. J Neurochem 1980; 34: 456–458.
Sherman WR, Leavitt AL, Honchar MP, Hallcher LM, Phillips BE . Evidence that lithium alters phosphoinositide metabolism: chronic administration elevates primarily D-myo-inositol-1-phosphate in cerebral cortex of the rat. J Neurochem 1981; 36: 1947–1951.
Lee CH, Dixon JF, Reichman M, Moummi C, Los G, Hokin LE . Li+ increases accumulation of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate in cholinergically stimulated brain cortex slices in guinea pig, mouse and rat. The increases require inositol supplementation in mouse and rat but not in guinea pig. Biochem J 1992; 282(Part 2): 377–385.
Dixon JF, Hokin LE . Lithium stimulates accumulation of second-messenger inositol 1,4,5-trisphosphate and other inositol phosphates in mouse pancreatic minilobules without inositol supplementation. Biochem J 1994; 304(Part 1): 251–258.
Hokin LE, Dixon JF, Los GV . A novel action of lithium: stimulation of glutamate release and inositol 1,4,5 trisphosphate accumulation via activation of the N-methyl D-aspartate receptor in monkey and mouse cerebral cortex slices. Adv Enzyme Regul 1996; 36: 229–244.
Sullivan NR, Burke T, Siafaka-Kapadai A, Javors M, Hensler JG . Effect of valproic acid on serotonin-2A receptor signaling in C6 glioma cells. J Neurochem 2004; 90: 1269–1275.
Kofman O, Belmaker RH . Intracerebroventricular myo-inositol antagonizes lithium-induced suppression of rearing behaviour in rats. Brain Res 1990; 534: 345–347.
Kofman O, Belmaker RH, Grisaru N, Alpert C, Fuchs I, Katz V et al. Myo-inositol attenuates two specific behavioral effects of acute lithium in rats. Psychopharmacol Bull 1991; 27: 185–190.
Kato T, Inubushi T, Kato N . Magnetic resonance spectroscopy in affective disorders. J Neuropsychiatry Clin Neurosci 1998; 10: 133–147.
Kato T, Shioiri T, Takahashi S, Inubushi T . Measurement of brain phosphoinositide metabolism in bipolar patients using in vivo 31P-MRS. J Affect Disord 1991; 22: 185–190.
Shimon H, Agam G, Belmaker RH, Hyde TM, Kleinman JE . Reduced frontal cortex inositol levels in postmortem brain of suicide victims and patients with bipolar disorder. Am J Psychiatry 1997; 154: 1148–1150.
Moore CM, Breeze JL, Gruber SA, Babb SM, Frederick BB, Villafuerte RA et al. Choline, myo-inositol and mood in bipolar disorder: a proton magnetic resonance spectroscopic imaging study of the anterior cingulate cortex. Bipolar Disord 2000; 2: 207–216.
Davanzo P, Thomas MA, Yue K, Oshiro T, Belin T, Strober M et al. Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder. Neuropsychopharmacology 2001; 24: 359–369.
Shapiro J, Belmaker RH, Biegon A, Seker A, Agam G . Scyllo-inositol in post-mortem brain of bipolar, unipolar and schizophrenic patients. J Neural Transm 2000; 107: 603–607.
Silverstone PH, Wu RH, O'Donnell T, Ulrich M, Asghar SJ, Hanstock CC . Chronic treatment with both lithium and sodium valproate may normalize phosphoinositol cycle activity in bipolar patients. Hum Psychopharmacol 2002; 17: 321–327.
Friedman SD, Dager SR, Parow A, Hirashima F, Demopulos C, Stoll AL et al. Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder. Biol Psychiatry 2004; 56: 340–348.
Belmaker RH, Shapiro J, Vainer E, Nemanov L, Ebstein RP, Agam G . Reduced inositol content in lymphocyte-derived cell lines from bipolar patients. Bipolar Disord 2002; 4: 67–69.
Banks RE, Aiton JF, Cramb G, Naylor GJ . Incorporation of inositol into the phosphoinositides of lymphoblastoid cell lines established from bipolar manic-depressive patients. J Affect Disord 1990; 19: 1–8.
Soares JC, Mallinger AG, Dippold CS, Forster Wells K, Frank E, Kupfer DJ . Effects of lithium on platelet membrane phosphoinositides in bipolar disorder patients: a pilot study. Psychopharmacology (Berlin) 2000; 149: 12–16.
Morain P, Lestage P, De Nanteuil G, Jochemsen R, Robin JL, Guez D et al. S 17092: a prolyl endopeptidase inhibitor as a potential therapeutic drug for memory impairment. Preclinical and clinical studies. CNS Drug Rev 2002; 8: 31–52.
Shinoda M, Miyazaki A, Toide K . Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on spatial memory and on cholinergic and peptidergic neurons in rats with ibotenate-induced lesions of the nucleus basalis magnocellularis. Behav Brain Res 1999; 99: 17–25.
Toide K, Iwamoto Y, Fujiwara T, Abe H . JTP-4819: a novel prolyl endopeptidase inhibitor with potential as a cognitive enhancer. J Pharmacol Exp Ther 1995; 274: 1370–1378.
Shishido Y, Furushiro M, Tanabe S, Nishiyama S, Hashimoto S, Ohno M et al. ZTTA, a postproline cleaving enzyme inhibitor, improves cerebral ischemia-induced deficits in a three-panel runway task in rats. Pharmacol Biochem Behav 1996; 55: 333–338.
Maes M, Goossens F, Scharpe S, Meltzer HY, D'Hondt P, Cosyns P . Lower serum prolyl endopeptidase enzyme activity in major depression: further evidence that peptidases play a role in the pathophysiology of depression. Biol Psychiatry 1994; 35: 545–552.
Maes M, Goossens F, Scharpe S, Calabrese J, Desnyder R, Meltzer HY . Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs. Psychiatry Res 1995; 58: 217–225.
Breen G, Harwood AJ, Gregory K, Sinclair M, Collier D, St Clair D et al. Two peptidase activities decrease in treated bipolar disorder not schizophrenic patients. Bipolar Disord 2004; 6: 156–161.
Majerus PW . Inositol phosphate biochemistry. Annu Rev Biochem 1992; 61: 225–250.
Gould E, Gross CG . Neurogenesis in adult mammals: some progress and problems. J Neurosci 2002; 22: 619–623.
Renshaw PF, Wicklund S . In vivo measurement of lithium in humans by nuclear magnetic resonance spectroscopy. Biol Psychiatry 1988; 23: 465–475.
Andreopoulos S, Wasserman M, Woo K, Li PP, Warsh JJ . Chronic lithium treatment of B lymphoblasts from bipolar disorder patients reduces transient receptor potential channel 3 levels. Pharmacogenomics J 2004; 4: 365–373.
Wasserman MJ, Corson TW, Sibony D, Cooke RG, Parikh SV, Pennefather PS et al. Chronic lithium treatment attenuates intracellular calcium mobilization. Neuropsychopharmacology 2004; 29: 759–769.
Mellor H, Parker PJ . The extended protein kinase C superfamily. Biochem J 1998; 332(Part 2): 281–292.
Nishizuka Y . Membrane phospholipid degradation and protein kinase C for cell signaling. Neurosci Res 1992; 15: 3–5.
Wang HY, Johnson GP, Friedman E . Lithium treatment inhibits protein kinase C translocation in rat brain cortex. Psychopharmacology (Berlin) 2001; 158: 80–86.
Wang H, Friedman E . Increased association of brain protein kinase C with the receptor for activated C kinase-1 (RACK1) in bipolar affective disorder. Biol Psychiatry 2001; 50: 364–370.
Lenox RH, Watson DG, Patel J, Ellis J . Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res 1992; 570: 333–340.
Manji HK, Lenox RH . Ziskind-Somerfeld Research Award. Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biol Psychiatry 1999; 46: 1328–1351.
Watson DG, Lenox RH . Chronic lithium-induced down-regulation of MARCKS in immortalized hippocampal cells: potentiation by muscarinic receptor activation. J Neurochem 1996; 67: 767–777.
Pacheco MA, Jope RS . Modulation of carbachol-stimulated AP-1 DNA binding activity by therapeutic agents for bipolar disorder in human neuroblastoma SH-SY5Y cells. Brain Res Mol Brain Res 1999; 72: 138–146.
Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M et al. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell 1991; 64: 573–584.
Manji HK, Moore GJ, Chen G . Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilizers. Br J Psychiatry Suppl 2001; 41: s107–s119.
York JD, Odom AR, Murphy R, Ives EB, Wente SR . A phospholipase C-dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export. Science 1999; 285: 96–100.
Shen X, Xiao H, Ranallo R, Wu WH, Wu C . Modulation of ATP-dependent chromatin-remodeling complexes by inositol polyphosphates. Science 2003; 299: 112–114.
Steger DJ, Haswell ES, Miller AL, Wente SR, O'Shea EK . Regulation of chromatin remodeling by inositol polyphosphates. Science 2003; 299: 114–116.
Rando OJ, Chi TH, Crabtree GR . Second messenger control of chromatin remodeling. Nat Struct Biol 2003; 10: 81–83.
Mora A, Komander D, van Aalten DM, Alessi DR . PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol 2004; 15: 161–170.
Levchenko A, Iglesias PA . Models of eukaryotic gradient sensing: application to chemotaxis of amoebae and neutrophils. Biophys J 2002; 82: 50–63.
van Horck FP, Lavazais E, Eickholt BJ, Moolenaar WH, Divecha N . Essential role of type I(alpha) phosphatidylinositol 4-phosphate 5-kinase in neurite remodeling. Curr Biol 2002; 12: 241–245.
Yamazaki M, Miyazaki H, Watanabe H, Sasaki T, Maehama T, Frohman MA et al. Phosphatidylinositol 4-phosphate 5-kinase is essential for ROCK-mediated neurite remodeling. J Biol Chem 2002; 277: 17226–17230.
Alvarez-Buylla A, Garcia-Verdugo JM, Tramontin AD . A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2001; 2: 287–293.
Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 2004; 427: 740–744.
van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH . Functional neurogenesis in the adult hippocampus. Nature 2002; 415: 1030–1034.
Williams R, Ryves JW, Dalton EC, Eickholt B, Shaltiel G, Agam G et al. A molecular cell biology of lithium. Biochem Soc Trans 2004; 32: 799–802.
Harrison PJ . The neuropathology of primary mood disorder. Brain 2002; 125: 1428–1449.
Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA . Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia. Nat Genet 2004; 36: 131–137.
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AJH is supported by a Wellcome Senior Biomedical Fellowship.
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Harwood, A. Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited. Mol Psychiatry 10, 117–126 (2005). https://doi.org/10.1038/sj.mp.4001618
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DOI: https://doi.org/10.1038/sj.mp.4001618
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