pp 1-40 | Cite as

Regulation of Inositol Biosynthesis: Balancing Health and Pathophysiology

  • Kendall C. Case
  • Michael Salsaa
  • Wenxi Yu
  • Miriam L. GreenbergEmail author
Part of the Handbook of Experimental Pharmacology book series


Inositol is the precursor for all inositol compounds and is essential for viability of eukaryotic cells. Numerous cellular processes and signaling functions are dependent on inositol compounds, and perturbation of their synthesis leads to a wide range of human diseases. Although considerable research has been directed at understanding the function of inositol compounds, especially phosphoinositides and inositol phosphates, a focus on regulatory and homeostatic mechanisms controlling inositol biosynthesis has been largely neglected. Consequently, little is known about how synthesis of inositol is regulated in human cells. Identifying physiological regulators of inositol synthesis and elucidating the molecular mechanisms that regulate inositol synthesis will contribute fundamental insight into cellular processes that are mediated by inositol compounds and will provide a foundation to understand numerous disease processes that result from perturbation of inositol homeostasis. In addition, elucidating the mechanisms of action of inositol-depleting drugs may suggest new strategies for the design of second-generation pharmaceuticals to treat psychiatric disorders and other illnesses.


Energy metabolism INO1 Inositol Inositol synthesis myo-inositol-3-phosphate synthase 



The Greenberg lab gratefully acknowledges support from grant R01 GM 125082 from the National Institutes of Health.


  1. Agam G, Bersudsky Y, Berry GT, Moechars D, Lavi-Avnon Y, Belmaker RH (2009) Knockout mice in understanding the mechanism of action of lithium. Biochem Soc Trans 37:1121–1125Google Scholar
  2. Ahmed S, Brickner DG, Light WH, Cajigas I, McDonough M, Froyshteter AB, Volpe T, Brickner JH (2010) DNA zip codes control an ancient mechanism for gene targeting to the nuclear periphery. Nat Cell Biol 12:111–118Google Scholar
  3. Aires CC, Soveral G, Luis PB, ten Brink HJ, de Almeida IT, Duran M, Wanders RJ, Silva MF (2008) Pyruvate uptake is inhibited by valproic acid and metabolites in mitochondrial membranes. FEBS Lett 582:3359–3366Google Scholar
  4. Aldinger F, Schulze TG (2017) Environmental factors, life events, and trauma in the course of bipolar disorder. Psychiatry Clin Neurosci 71:6–17Google Scholar
  5. Ambroziak J, Henry SA (1994) INO2 and INO4 gene products, positive regulators of phospholipid biosynthesis in Saccharomyces cerevisiae, form a complex that binds to the INO1 promoter. J Biol Chem 269:15344–15349Google Scholar
  6. Artini PG, Di Berardino OM, Papini F, Genazzani AD, Simi G, Ruggiero M, Cela V (2013) Endocrine and clinical effects of myo-inositol administration in polycystic ovary syndrome. A randomized study. Gynecol Endocrinol 29:375–379Google Scholar
  7. Ashburner BP, Lopes JM (1995) Autoregulated expression of the yeast INO2 and INO4 helix-loop-helix activator genes effects cooperative regulation on their target genes. Mol Cell Biol 15:1709–1715Google Scholar
  8. Atack JR, Cook SM, Watt AP, Fletcher SR, Ragan CI (1993) In vitro and in vivo inhibition of inositol monophosphatase by the bisphosphonate L-690,330. J Neurochem 60:652–658Google Scholar
  9. Avery LB, Bumpus NN (2014) Valproic acid is a novel activator of AMP-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice. Mol Pharmacol 85:1–10Google Scholar
  10. Azab AN, He Q, Ju S, Li G, Greenberg ML (2007) Glycogen synthase kinase-3 is required for optimal de novo synthesis of inositol. Mol Microbiol 63:1248–1258Google Scholar
  11. Azab A, Agam G, Kaplanski J, Delbar V, Greenberg ML (2008) Inositol depletion: a good or bad outcome of valproate treatment? Future Neurol 3:275–286Google Scholar
  12. Bachhawat N, Ouyang Q, Henry SA (1995) Functional characterization of an inositol-sensitive upstream activation sequence in yeast. A cis-regulatory element responsible for inositol-choline mediated regulation of phospholipid biosynthesis. J Biol Chem 270:25087–25095Google Scholar
  13. Bailis AM, Poole MA, Carman GM, Henry SA (1987) The membrane-associated enzyme phosphatidylserine synthase is regulated at the level of mRNA abundance. Mol Cell Biol 7:167–176Google Scholar
  14. Baillargeon JP, Diamanti-Kandarakis E, Ostlund RE Jr, Apridonidze T, Iuorno MJ, Nestler JE (2006) Altered D-chiro-inositol urinary clearance in women with polycystic ovary syndrome. Diabetes Care 29:300–305Google Scholar
  15. Baillargeon JP, Iuorno MJ, Apridonidze T, Nestler JE (2010) Uncoupling between insulin and release of a D-chiro-inositol-containing inositolphosphoglycan mediator of insulin action in obese women with polycystic ovary syndrome. Metab Syndr Relat Disord 8:127–136Google Scholar
  16. Beaulieu JM, Sotnikova TD, Yao WD, Kockeritz L, Woodgett JR, Gainetdinov RR, Caron MG (2004) Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci U S A 101:5099–5104Google Scholar
  17. Belmaker RH, Bersudsky Y, Agam G, Levine J, Kofman O (1996) How does lithium work on manic depression? Clinical and psychological correlates of the inositol theory. Annu Rev Med 47:47–56Google Scholar
  18. Benelli E, Del Ghianda S, Di Cosmo C, Tonacchera M (2016) A combined therapy with myo-inositol and D-chiro-inositol improves endocrine parameters and insulin resistance in PCOS young overweight women. Int J Endocrinol 2016:3204083Google Scholar
  19. Bergeron R, Ren JM, Cadman KS, Moore IK, Perret P, Pypaert M, Young LH, Semenkovich CF, Shulman GI (2001) Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab 281:E1340–E1346Google Scholar
  20. Berridge MJ (2014) Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia. Cell Tissue Res 357:477–492Google Scholar
  21. Berridge MJ, Irvine RF (1989) Inositol phosphates and cell signalling. Nature 341:197–205Google Scholar
  22. Berridge MJ, Downes CP, Hanley MR (1982) Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem J 206:587–595Google Scholar
  23. Berry GT, Wu S, Buccafusca R, Ren J, Gonzales LW, Ballard PL, Golden JA, Stevens MJ, Greer JJ (2003) Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea. J Biol Chem 278:18297–18302Google Scholar
  24. Berry GT, Buccafusca R, Greer JJ, Eccleston E (2004) Phosphoinositide deficiency due to inositol depletion is not a mechanism of lithium action in brain. Mol Genet Metab 82:87–92Google Scholar
  25. Bizzarri M, Fuso A, Dinicola S, Cucina A, Bevilacqua A (2016) Pharmacodynamics and pharmacokinetics of inositol(s) in health and disease. Expert Opin Drug Metab Toxicol 12:1181–1196Google Scholar
  26. Blanco C, Compton WM, Saha TD, Goldstein BI, Ruan WJ, Huang B, Grant BF (2017) Epidemiology of DSM-5 bipolar I disorder: results from the National Epidemiologic Survey on alcohol and related conditions-III. J Psychiatr Res 84:310–317Google Scholar
  27. Blazer DG, Kessler RC, McGonagle KA, Swartz MS (1994) The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry 151:979–986Google Scholar
  28. Bosch F, Rodriguez-Gil JE, Hatzoglou M, Gomez-Foix AM, Hanson RW (1992) Lithium inhibits hepatic gluconeogenesis and phosphoenolpyruvate carboxykinase gene expression. J Biol Chem 267:2888–2893Google Scholar
  29. Bourgeois F, Coady MJ, Lapointe JY (2005) Determination of transport stoichiometry for two cation-coupled myo-inositol cotransporters: SMIT2 and HMIT. J Physiol 563:333–343Google Scholar
  30. Bown CD, Wang JF, Chen B, Young LT (2002) Regulation of ER stress proteins by valproate: therapeutic implications. Bipolar Disord 4:145–151Google Scholar
  31. Brand A, Richter-Landsberg C, Leibfritz D (1993) Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 15:289–298Google Scholar
  32. Brickner JH, Walter P (2004) Gene recruitment of the activated INO1 locus to the nuclear membrane. PLoS Biol 2:e342Google Scholar
  33. Brown AS, Mallinger AG, Renbaum LC (1993) Elevated platelet membrane phosphatidylinositol-4,5-bisphosphate in bipolar mania. Am J Psychiatry 150:1252–1254Google Scholar
  34. Burton LE, Ray RE, Bradford JR, Orr JP, Nickerson JA, Wells WW (1976) Myo-inositol metabolism in the neonatal and developing rat fed a myo-inositol-free diet. J Nutr 106:1610–1616Google Scholar
  35. Burton A, Azevedo C, Andreassi C, Riccio A, Saiardi A (2013) Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation. Proc Natl Acad Sci U S A 110:18970–18975Google Scholar
  36. Caetano SC, Fonseca M, Olvera RL, Nicoletti M, Hatch JP, Stanley JA, Hunter K, Lafer B, Pliszka SR, Soares JC (2005) Proton spectroscopy study of the left dorsolateral prefrontal cortex in pediatric depressed patients. Neurosci Lett 384:321–326Google Scholar
  37. Can A, Dao DT, Arad M, Terrillion CE, Piantadosi SC, Gould TD (2012) The mouse forced swim test. J Vis Exp 59:e3638Google Scholar
  38. Cardenas C, Miller RA, Smith I, Bui T, Molgo J, Muller M, Vais H, Cheung KH, Yang J, Parker I, Thompson CB, Birnbaum MJ, Hallows KR, Foskett JK (2010) Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142:270–283Google Scholar
  39. Carlomagno G, Nordio M, Chiu TT, Unfer V (2011) Contribution of myo-inositol and melatonin to human reproduction. Eur J Obstet Gynecol Reprod Biol 159:267–272Google Scholar
  40. Carman GM, Han G-S (2011) Regulation of phospholipid synthesis in the yeast Saccharomyces cerevisiae. Annu Rev Biochem 80:859–883Google Scholar
  41. Cataldo AM, McPhie DL, Lange NT, Punzell S, Elmiligy S, Ye NZ, Froimowitz MP, Hassinger LC, Menesale EB, Sargent LW, Logan DJ, Carpenter AE, Cohen BM (2010) Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. Am J Pathol 177:575–585Google Scholar
  42. Celik C, Tasdemir N, Abali R, Bastu E, Yilmaz M (2014) Progression to impaired glucose tolerance or type 2 diabetes mellitus in polycystic ovary syndrome: a controlled follow-up study. Fertil Steril 101:1123–1128.e1Google Scholar
  43. Chakraborty A, Koldobskiy MA, Bello NT, Maxwell M, Potter JJ, Juluri KR, Maag D, Kim S, Huang AS, Dailey MJ, Saleh M, Snowman AM, Moran TH, Mezey E, Snyder SH (2010) Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. Cell 143:897–910Google Scholar
  44. Chakraborty A, Latapy C, Xu J, Snyder SH, Beaulieu JM (2014) Inositol hexakisphosphate kinase-1 regulates behavioral responses via GSK3 signaling pathways. Mol Psychiatry 19:284–293Google Scholar
  45. Chaube B, Malvi P, Singh SV, Mohammad N, Viollet B, Bhat MK (2015) AMPK maintains energy homeostasis and survival in cancer cells via regulating p38/PGC-1alpha-mediated mitochondrial biogenesis. Cell Death Discovery 1:15063Google Scholar
  46. Chen I-W, Charalampous FC (1966) Biochemical studies on inositol IX. D-inositol 1-phosphate as intermediate in the biosynthesis of inositol from glucose 6-phosphate, and characteristics of two reactions in this biosynthesis. J Biol Chem 241:2194–2199Google Scholar
  47. Chen G, Huang LD, Jiang YM, Manji HK (1999) The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem 72:1327–1330Google Scholar
  48. Chen LP, Dai HY, Dai ZZ, Xu CT, Wu RH (2014) Anterior cingulate cortex and cerebellar hemisphere neurometabolite changes in depression treatment: a 1H magnetic resonance spectroscopy study. Psychiatry Clin Neurosci 68:357–364Google Scholar
  49. Chesney E, Goodwin GM, Fazel S (2014) Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry 13:153–160Google Scholar
  50. Chiappelli J, Rowland LM, Wijtenburg SA, Muellerklein F, Tagamets M, McMahon RP, Gaston F, Kochunov P, Hong LE (2015) Evaluation of myo-inositol as a potential biomarker for depression in schizophrenia. Neuropsychopharmacology 40:2157–2164Google Scholar
  51. Chinta SJ, Andersen JK (2005) Dopaminergic neurons. Int J Biochem Cell Biol 37:942–946Google Scholar
  52. Chiu TT, Rogers MS, Law EL, Briton-Jones CM, Cheung LP, Haines CJ (2002) Follicular fluid and serum concentrations of myo-inositol in patients undergoing IVF: relationship with oocyte quality. Hum Reprod 17:1591–1596Google Scholar
  53. Choi K, Mollapour E, Choi JH, Shears SB (2008) Cellular energetic status supervises the synthesis of bis-diphosphoinositol tetrakisphosphate independently of AMP-activated protein kinase. Mol Pharmacol 74:527–536Google Scholar
  54. Ciani L, Salinas PC (2005) WNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci 6:351–362Google Scholar
  55. Clark JB (1998) N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 20:271–276Google Scholar
  56. Coupland NJ, Ogilvie CJ, Hegadoren KM, Seres P, Hanstock CC, Allen PS (2005) Decreased prefrontal myo-inositol in major depressive disorder. Biol Psychiatry 57:1526–1534Google Scholar
  57. Cox JS, Walter P (1996) A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell 87:391–404Google Scholar
  58. Cox JS, Chapman RE, Walter P (1997) The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane. Mol Biol Cell 8:1805–1814Google Scholar
  59. Craddock N, Sklar P (2013) Genetics of bipolar disorder. Lancet 381:1654–1662Google Scholar
  60. Criollo A, Maiuri MC, Tasdemir E, Vitale I, Fiebig AA, Andrews D, Molgo J, Diaz J, Lavandero S, Harper F, Pierron G, di Stefano D, Rizzuto R, Szabadkai G, Kroemer G (2007) Regulation of autophagy by the inositol trisphosphate receptor. Cell Death Differ 14:1029–1039Google Scholar
  61. Croze ML, Soulage CO (2013) Potential role and therapeutic interests of myo-inositol in metabolic diseases. Biochimie 95:1811–1827Google Scholar
  62. Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245Google Scholar
  63. Czech MP (2003) Dynamics of phosphoinositides in membrane retrieval and insertion. Annu Rev Physiol 65:791–815Google Scholar
  64. Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL, Lyoo IK, Dunner DL, Renshaw PF (2004) Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry 61:450–458Google Scholar
  65. Dasgupta A, Juedes SA, Sprouse RO, Auble DT (2005) Mot1-mediated control of transcription complex assembly and activity. EMBO J 24:1717–1729Google Scholar
  66. Dayalu P, Albin RL (2015) Huntington disease: pathogenesis and treatment. Neurol Clin 33:101–114Google Scholar
  67. De Stefano N, Matthews PM, Arnold DL (1995) Reversible decreases in N-acetylaspartate after acute brain injury. Magn Reson Med 34:721–727Google Scholar
  68. Deranieh RM, Greenberg ML (2009) Cellular consequences of inositol depletion. Biochem Soc Trans 37:1099–1103Google Scholar
  69. Deranieh RM, He Q, Caruso JA, Greenberg ML (2013) Phosphorylation regulates myo-inositol-3-phosphate synthase: a novel regulatory mechanism of inositol biosynthesis. J Biol Chem 288:26822–26833Google Scholar
  70. Dey NB, Bounelis P, Fritz TA, Bedwell DM, Marchase RB (1994) The glycosylation of phosphoglucomutase is modulated by carbon source and heat shock in Saccharomyces cerevisiae. J Biol Chem 269:27143–27148Google Scholar
  71. Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657Google Scholar
  72. Dietz M, Heyken WT, Hoppen J, Geburtig S, Schuller HJ (2003) TFIIB and subunits of the SAGA complex are involved in transcriptional activation of phospholipid biosynthetic genes by the regulatory protein Ino2 in the yeast Saccharomyces cerevisiae. Mol Microbiol 48:1119–1130Google Scholar
  73. Dinicola S, Chiu TT, Unfer V, Carlomagno G, Bizzarri M (2014) The rationale of the myo-inositol and D-chiro-inositol combined treatment for polycystic ovary syndrome. J Clin Pharmacol 54:1079–1092Google Scholar
  74. Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175–1186Google Scholar
  75. Donahue TF, Henry SA (1981) Myo-inositol-1-phosphate synthase. Characteristics of the enzyme and identification of its structural gene in yeast. J Biol Chem 256:7077–7085Google Scholar
  76. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461Google Scholar
  77. Facchinetti F, Bizzarri M, Benvenga S, D’Anna R, Lanzone A, Soulage C, Di Renzo GC, Hod M, Cavalli P, Chiu TT, Kamenov ZA, Bevilacqua A, Carlomagno G, Gerli S, Oliva MM, Devroey P (2015) Results from the international consensus conference on myo-inositol and D-chiro-inositol in obstetrics and gynecology: the link between metabolic syndrome and PCOS. Eur J Obstet Gynecol Reprod Biol 195:72–76Google Scholar
  78. Fernandez-Marcos PJ, Auwerx J (2011) Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 93:884S–890SGoogle Scholar
  79. Fisher SK, Novak JE, Agranoff BW (2002) Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance. J Neurochem 82:736–754Google Scholar
  80. Ford J, Odeyale O, Eskandar A, Kouba N, Shen C-H (2007) A SWI/SNF-and INO80-dependent nucleosome movement at the INO1 promoter. Biochem Biophys Res Commun 361:974–979Google Scholar
  81. Ford J, Odeyale O, Shen C-H (2008) Activator-dependent recruitment of SWI/SNF and INO80 during INO1 activation. Biochem Biophys Res Commun 373:602–606Google Scholar
  82. Frey R, Metzler D, Fischer P, Heiden A, Scharfetter J, Moser E, Kasper S (1998) Myo-inositol in depressive and healthy subjects determined by frontal 1H-magnetic resonance spectroscopy at 1.5 tesla. J Psychiatr Res 32:411–420Google Scholar
  83. Fu H, Li B, Hertz L, Peng L (2012) Contributions in astrocytes of SMIT1/2 and HMIT to myo-inositol uptake at different concentrations and pH. Neurochem Int 61:187–194Google Scholar
  84. Gaspar ML, Chang Y-F, Jesch SA, Aregullin M, Henry SA (2017) Interaction between repressor Opi1p and ER membrane protein Scs2p facilitates transit of phosphatidic acid from the ER to mitochondria and is essential for INO1 gene expression in the presence of choline. J Biol Chem M117:809970Google Scholar
  85. Geiger JH, Jin X (2006) The structure and mechanism of myo-inositol-1-phosphate synthase. Subcell Biochem 39:157Google Scholar
  86. Gelbart ME, Bachman N, Delrow J, Boeke JD, Tsukiyama T (2005) Genome-wide identification of Isw2 chromatin-remodeling targets by localization of a catalytically inactive mutant. Genes Dev 19:942–954Google Scholar
  87. Genazzani AD (2016) Inositol as putative integrative treatment for PCOS. Reprod Biomed Online 33:770–780Google Scholar
  88. Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM (2008) Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecol Endocrinol 24:139–144Google Scholar
  89. Genazzani AD, Prati A, Santagni S, Ricchieri F, Chierchia E, Rattighieri E, Campedelli A, Simoncini T, Artini PG (2012) Differential insulin response to myo-inositol administration in obese polycystic ovary syndrome patients. Gynecol Endocrinol 28:969–973Google Scholar
  90. Genazzani AD, Santagni S, Rattighieri E, Chierchia E, Despini G, Marini G, Prati A, Simoncini T (2014) Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients. Gynecol Endocrinol 30:438–443Google Scholar
  91. Gerli S, Mignosa M, Di Renzo GC (2003) Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Eur Rev Med Pharmacol Sci 7:151–159Google Scholar
  92. Gerli S, Papaleo E, Ferrari A, Di Renzo GC (2007) Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS. Eur Rev Med Pharmacol Sci 11:347–354Google Scholar
  93. Goldmark JP, Fazzio TG, Estep PW, Church GM, Tsukiyama T (2000) The Isw2 chromatin remodeling complex represses early meiotic genes upon recruitment by Ume6p. Cell 103:423–433Google Scholar
  94. Gould TD, Einat H, Bhat R, Manji HK (2004) AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. Int J Neuropsychopharmacol 7:387–390Google Scholar
  95. Gould TD, Einat H, O’Donnell KC, Picchini AM, Schloesser RJ, Manji HK (2007) Beta-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors. Neuropsychopharmacology 32:2173–2183Google Scholar
  96. Graves JA, Henry SA (2000) Regulation of the yeast INO1 gene. The products of the INO2, INO4 and OPI1 regulatory genes are not required for repression in response to inositol. Genetics 154:1485–1495Google Scholar
  97. Greenberg ML, Lopes JM (1996) Genetic regulation of phospholipid biosynthesis in Saccharomyces cerevisiae. Microbiol Rev 60:1Google Scholar
  98. Greenberg ML, Goldwasser P, Henry SA (1982) Characterization of a yeast regulatory mutant constitutive for synthesis of inositol-1-phosphate synthase. Mol Gen Genet 186:157–163Google Scholar
  99. Griffin JL, Bollard M, Nicholson JK, Bhakoo K (2002) Spectral profiles of cultured neuronal and glial cells derived from HRMAS (1)H NMR spectroscopy. NMR Biomed 15:375–384Google Scholar
  100. Groger A, Kolb R, Schafer R, Klose U (2014) Dopamine reduction in the substantia nigra of Parkinson’s disease patients confirmed by in vivo magnetic resonance spectroscopic imaging. PLoS One 9:e84081Google Scholar
  101. Hager K, Hazama A, Kwon HM, Loo DD, Handler JS, Wright EM (1995) Kinetics and specificity of the renal Na+/myo-inositol cotransporter expressed in Xenopus oocytes. J Membr Biol 143:103–113Google Scholar
  102. Hajek T, Carrey N, Alda M (2005) Neuroanatomical abnormalities as risk factors for bipolar disorder. Bipolar Disord 7:393–403Google Scholar
  103. Hall AC, Brennan A, Goold RG, Cleverley K, Lucas FR, Gordon-Weeks PR, Salinas PC (2002) Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons. Mol Cell Neurosci 20:257–270Google Scholar
  104. Hamakawa H, Murashita J, Yamada N, Inubushi T, Kato N, Kato T (2004) Reduced intracellular pH in the basal ganglia and whole brain measured by 31P-MRS in bipolar disorder. Psychiatry Clin Neurosci 58:82–88Google Scholar
  105. Haneda M, Kikkawa R, Arimura T, Ebata K, Togawa M, Maeda S, Sawada T, Horide N, Shigeta Y (1990) Glucose inhibits myo-inositol uptake and reduces myo-inositol content in cultured rat glomerular mesangial cells. Metabolism 39:40–45Google Scholar
  106. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889Google Scholar
  107. Hayashi A, Kasahara T, Kametani M, Toyota T, Yoshikawa T, Kato T (2009) Aberrant endoplasmic reticulum stress response in lymphoblastoid cells from patients with bipolar disorder. Int J Neuropsychopharmacol 12:33–43Google Scholar
  108. Hayes JF, Miles J, Walters K, King M, Osborn DP (2015) A systematic review and meta-analysis of premature mortality in bipolar affective disorder. Acta Psychiatr Scand 131:417–425Google Scholar
  109. Heyken WT, Repenning A, Kumme J, Schuller HJ (2005) Constitutive expression of yeast phospholipid biosynthetic genes by variants of Ino2 activator defective for interaction with Opi1 repressor. Mol Microbiol 56:696–707Google Scholar
  110. Hirata Y, Andoh T, Asahara T, Kikuchi A (2003) Yeast glycogen synthase kinase-3 activates Msn2p-dependent transcription of stress responsive genes. Mol Biol Cell 14:302–312Google Scholar
  111. Hofbauer HF, Schopf FH, Schleifer H, Knittelfelder OL, Pieber B, Rechberger GN, Wolinski H, Gaspar ML, Kappe CO, Stadlmann J, Mechtler K, Zenz A, Lohner K, Tehlivets O, Henry SA, Kohlwein SD (2014) Regulation of gene expression through a transcriptional repressor that senses acyl-chain length in membrane phospholipids. Dev Cell 29:729–739Google Scholar
  112. Hoshizaki DK, Hill JE, Henry SA (1990) The Saccharomyces cerevisiae INO4 gene encodes a small, highly basic protein required for derepression of phospholipid biosynthetic enzymes. J Biol Chem 265:4736–4745Google Scholar
  113. Huang LC, Fonteles MC, Houston DB, Zhang C, Larner J (1993) Chiroinositol deficiency and insulin resistance. III. Acute glycogenic and hypoglycemic effects of two inositol phosphoglycan insulin mediators in normal and streptozotocin-diabetic rats in vivo. Endocrinology 132:652–657Google Scholar
  114. Hudecova M, Holte J, Olovsson M, Larsson A, Berne C, Poromaa IS (2011) Diabetes and impaired glucose tolerance in patients with polycystic ovary syndrome – a long term follow-up. Hum Reprod 26:1462–1468Google Scholar
  115. Hur EM, Zhou FQ (2010) GSK3 signalling in neural development. Nat Rev Neurosci 11:539–551Google Scholar
  116. Ibsen L, Strange K (1996) In situ localization and osmotic regulation of the Na(+)-myo-inositol cotransporter in rat brain. Am J Phys 271:F877–F885Google Scholar
  117. Iuorno MJ, Jakubowicz DJ, Baillargeon JP, Dillon P, Gunn RD, Allan G, Nestler JE (2002) Effects of D-chiro-inositol in lean women with the polycystic ovary syndrome. Endocr Pract 8:417–423Google Scholar
  118. Jadhav S, Russo S, Cottier S, Schneiter R, Cowart A, Greenberg ML (2016) Valproate induces the unfolded protein response by increasing ceramide levels. J Biol Chem 291:22253–22261Google Scholar
  119. Jager S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 104:12017–12022Google Scholar
  120. Jaschke Y, Schwarz J, Clausnitzer D, Muller C, Schuller HJ (2011) Pleiotropic corepressors Sin3 and Ssn6 interact with repressor Opi1 and negatively regulate transcription of genes required for phospholipid biosynthesis in the yeast Saccharomyces cerevisiae. Mol Gen Genomics 285:91–100Google Scholar
  121. Jenkins R, Lewis G, Bebbington P, Brugha T, Farrell M, Gill B, Meltzer H (1997) The National Psychiatric Morbidity surveys of Great Britain – initial findings from the household survey. Psychol Med 27:775–789Google Scholar
  122. Jesch SA, Zhao X, Wells MT, Henry SA (2005) Genome-wide analysis reveals inositol, not choline, as the major effector of Ino2p-Ino4p and unfolded protein response target gene expression in yeast. J Biol Chem 280:9106–9118Google Scholar
  123. Jonathan Ryves W, Dalton EC, Harwood AJ, Williams RS (2005) GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid. Bipolar Disord 7:260–265Google Scholar
  124. Jope RS (2003) Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci 24:441–443Google Scholar
  125. Jope RS, Johnson GV (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29:95–102Google Scholar
  126. Jope RS, Song L, Li PP, Young LT, Kish SJ, Pacheco MA, Warsh JJ (1996) The phosphoinositide signal transduction system is impaired in bipolar affective disorder brain. J Neurochem 66:2402–2409Google Scholar
  127. Ju S, Greenberg ML (2003) Valproate disrupts regulation of inositol responsive genes and alters regulation of phospholipid biosynthesis. Mol Microbiol 49:1595–1603Google Scholar
  128. Kadosh D, Struhl K (1997) Repression by Ume6 involves recruitment of a complex containing Sin3 corepressor and Rpd3 histone deacetylase to target promoters. Cell 89:365–371Google Scholar
  129. Kaidanovich-Beilin O, Milman A, Weizman A, Pick CG, Eldar-Finkelman H (2004) Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus. Biol Psychiatry 55:781–784Google Scholar
  130. Kakiuchi C, Iwamoto K, Ishiwata M, Bundo M, Kasahara T, Kusumi I, Tsujita T, Okazaki Y, Nanko S, Kunugi H, Sasaki T, Kato T (2003) Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet 35:171–175Google Scholar
  131. Kato T (2008) Role of mitochondrial DNA in calcium signaling abnormality in bipolar disorder. Cell Calcium 44:92–102Google Scholar
  132. Kato T, Kato N (2000) Mitochondrial dysfunction in bipolar disorder. Bipolar Disord 2:180–190Google Scholar
  133. Kato T, Shioiri T, Murashita J, Hamakawa H, Inubushi T, Takahashi S (1994) Phosphorus-31 magnetic resonance spectroscopy and ventricular enlargement in bipolar disorder. Psychiatry Res 55:41–50Google Scholar
  134. Kato T, Shioiri T, Murashita J, Hamakawa H, Takahashi Y, Inubushi T, Takahashi S (1995) Lateralized abnormality of high energy phosphate metabolism in the frontal lobes of patients with bipolar disorder detected by phase-encoded 31P-MRS. Psychol Med 25:557–566Google Scholar
  135. Kato T, Murashita J, Kamiya A, Shioiri T, Kato N, Inubushi T (1998) Decreased brain intracellular pH measured by 31P-MRS in bipolar disorder: a confirmation in drug-free patients and correlation with white matter hyperintensity. Eur Arch Psychiatry Clin Neurosci 248:301–306Google Scholar
  136. Kato T, Kunugi H, Nanko S, Kato N (2000) Association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA. Am J Med Genet 96:182–186Google Scholar
  137. Kato T, Kunugi H, Nanko S, Kato N (2001) Mitochondrial DNA polymorphisms in bipolar disorder. J Affect Disord 62:151–164Google Scholar
  138. Kennington AS, Hill CR, Craig J, Bogardus C, Raz I, Ortmeyer HK, Hansen BC, Romero G, Larner J (1990) Low urinary chiro-inositol excretion in non-insulin-dependent diabetes mellitus. N Engl J Med 323:373–378Google Scholar
  139. Kim AJ, Shi Y, Austin RC, Werstuck GH (2005) Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3. J Cell Sci 118:89–99Google Scholar
  140. Klein PS, Melton DA (1996) A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A 93:8455–8459Google Scholar
  141. Klig LS, Henry SA (1984) Isolation of the yeast INO1 gene: located on an autonomously replicating plasmid, the gene is fully regulated. Proc Natl Acad Sci U S A 81:3816–3820Google Scholar
  142. Klig LS, Homann MJ, Carman GM, Henry SA (1985) Coordinate regulation of phospholipid biosynthesis in Saccharomyces cerevisiae: pleiotropically constitutive opi1 mutant. J Bacteriol 162:1135–1141Google Scholar
  143. Koch-Weser J, O’Malley K, O’Brien E (1980) Drug therapy: management of hypertension in the elderly. N Engl J Med 302:1397–1401Google Scholar
  144. Kofman O, Belmaker RH (1990) Intracerebroventricular myo-inositol antagonizes lithium-induced suppression of rearing behaviour in rats. Brain Res 534:345–347Google Scholar
  145. Kollros PE, Goldstein GW, Betz AL (1990) Myo-inositol transport into endothelial cells derived from nervous system microvessels. Brain Res 511:259–264Google Scholar
  146. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884Google Scholar
  147. Komulainen T, Lodge T, Hinttala R, Bolszak M, Pietila M, Koivunen P, Hakkola J, Poulton J, Morten KJ, Uusimaa J (2015) Sodium valproate induces mitochondrial respiration dysfunction in HepG2 in vitro cell model. Toxicology 331:47–56Google Scholar
  148. Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C, Shokat KM, Stroud RM, Walter P (2009) The unfolded protein response signals through high-order assembly of Ire1. Nature 457:687–693Google Scholar
  149. Kumme J, Dietz M, Wagner C, Schuller HJ (2008) Dimerization of yeast transcription factors Ino2 and Ino4 is regulated by precursors of phospholipid biosynthesis mediated by Opi1 repressor. Curr Genet 54:35–45Google Scholar
  150. La Marca A, Grisendi V, Dondi G, Sighinolfi G, Cianci A (2015) The menstrual cycle regularization following D-chiro-inositol treatment in PCOS women: a retrospective study. Gynecol Endocrinol 31:52–56Google Scholar
  151. Lagana AS, Barbaro L, Pizzo A (2015) Evaluation of ovarian function and metabolic factors in women affected by polycystic ovary syndrome after treatment with D-chiro-inositol. Arch Gynecol Obstet 291:1181–1186Google Scholar
  152. Lai K, McGraw P (1994) Dual control of inositol transport in Saccharomyces cerevisiae by irreversible inactivation of permease and regulation of permease synthesis by INO2, INO4, and OPI1. J Biol Chem 269:2245–2251Google Scholar
  153. Lai E, Teodoro T, Volchuk A (2007) Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology (Bethesda) 22:193–201Google Scholar
  154. Larner J (2002) D-chiro-inositol – its functional role in insulin action and its deficit in insulin resistance. Int J Exp Diabetes Res 3:47–60Google Scholar
  155. Larner J, Craig JW (1996) Urinary myo-inositol-to-chiro-inositol ratios and insulin resistance. Diabetes Care 19:76–78Google Scholar
  156. Larner J, Brautigan DL, Thorner MO (2010) D-chiro-inositol glycans in insulin signaling and insulin resistance. Mol Med 16:543–552Google Scholar
  157. Leboyer M, Soreca I, Scott J, Frye M, Henry C, Tamouza R, Kupfer DJ (2012) Can bipolar disorder be viewed as a multi-system inflammatory disease? J Affect Disord 141:1–10Google Scholar
  158. Lee MH, Hong I, Kim M, Lee BH, Kim JH, Kang KS, Kim HL, Yoon BI, Chung H, Kong G, Lee MO (2007) Gene expression profiles of murine fatty liver induced by the administration of valproic acid. Toxicol Appl Pharmacol 220:45–59Google Scholar
  159. Levine J (1997) Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol 7:147–155Google Scholar
  160. Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477Google Scholar
  161. Levine J, Rapaport A, Lev L, Bersudsky Y, Kofman O, Belmaker RH, Shapiro J, Agam G (1993) Inositol treatment raises CSF inositol levels. Brain Res 627:168–170Google Scholar
  162. Levine J, Barak Y, Gonzalves M, Szor H, Elizur A, Kofman O, Belmaker RH (1995) Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry 152:792–794Google Scholar
  163. Lewis JH, Zimmerman HJ, Garrett CT, Rosenberg E (1982) Valproate-induced hepatic steatogenesis in rats. Hepatology 2:870–873Google Scholar
  164. Li XZ, Chen XP, Zhao K, Bai LM, Zhang H, Zhou XP (2013) Therapeutic effects of valproate combined with lithium carbonate on MPTP-induced parkinsonism in mice: possible mediation through enhanced autophagy. Int J Neurosci 123:73–79Google Scholar
  165. Li L, Gu Z, Liu Z, Su L (2014) The effect of reactive oxygen species regulation of expression of Bcl-2 and Bax in apoptosis of human umbilical vein endothelial cell induced by heat stress. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 26:458–463Google Scholar
  166. Li CT, Bai YM, Hsieh JC, Lee HC, Yang BH, Chen MH, Lin WC, Tsai CF, Tu PC, Wang SJ, Su TP (2015) Peripheral and central glucose utilizations modulated by mitochondrial DNA 10398A in bipolar disorder. Psychoneuroendocrinology 55:72–80Google Scholar
  167. Linares GR, Chiu CT, Scheuing L, Leng Y, Liao HM, Maric D, Chuang DM (2016) Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington’s disease. Exp Neurol 281:81–92Google Scholar
  168. Lionaki E, Markaki M, Palikaras K, Tavernarakis N (2015) Mitochondria, autophagy and age-associated neurodegenerative diseases: new insights into a complex interplay. Biochim Biophys Acta 1847:1412–1423Google Scholar
  169. Lirng JF, Chen HC, Fuh JL, Tsai CF, Liang JF, Wang SJ (2015) Increased myo-inositol level in dorsolateral prefrontal cortex in migraine patients with major depression. Cephalalgia 35:702–709Google Scholar
  170. Lo WS, Duggan L, Emre NC, Belotserkovskya R, Lane WS, Shiekhattar R, Berger SL (2001) Snf1 – a histone kinase that works in concert with the histone acetyltransferase Gcn5 to regulate transcription. Science 293:1142–1146Google Scholar
  171. Lo WS, Gamache ER, Henry KW, Yang D, Pillus L, Berger SL (2005) Histone H3 phosphorylation can promote TBP recruitment through distinct promoter-specific mechanisms. EMBO J 24:997–1008Google Scholar
  172. Lochhead PA, Coghlan M, Rice SQ, Sutherland C (2001) Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression. Diabetes 50:937–946Google Scholar
  173. Loewen CJ, Roy A, Levine TP (2003) A conserved ER targeting motif in three families of lipid binding proteins and in Opi1p binds VAP. EMBO J 22:2025–2035Google Scholar
  174. Loewy BS, Henry SA (1984) The INO2 and INO4 loci of Saccharomyces cerevisiae are pleiotropic regulatory genes. Mol Cell Biol 4:2479–2485Google Scholar
  175. Lopes JM, Henry SA (1991) Interaction of trans and cis regulatory elements in the INO1 promoter of Saccharomyces cerevisiae. Nucleic Acids Res 19:3987–3994Google Scholar
  176. Lopes JM, Hirsch JP, Chorgo PA, Schulze KL, Henry SA (1991) Analysis of sequences in the INO1 promoter that are involved in its regulation by phospholipid precursors. Nucleic Acids Res 19:1687–1693Google Scholar
  177. Lopes J, Schulze K, Yates J, Hirsch J, Henry S (1993) The INO1 promoter of Saccharomyces cerevisiae includes an upstream repressor sequence (URS1) common to a diverse set of yeast genes. J Bacteriol 175:4235–4238Google Scholar
  178. Lovestone S, Davis DR, Webster MT, Kaech S, Brion JP, Matus A, Anderton BH (1999) Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations. Biol Psychiatry 45:995–1003Google Scholar
  179. Lubrich B, van Calker D (1999) Inhibition of the high affinity myo-inositol transport system: a common mechanism of action of antibipolar drugs? Neuropsychopharmacology 21:519–529Google Scholar
  180. Lubrich B, Spleiss O, Gebicke-Haerter PJ, van Calker D (2000) Differential expression, activity and regulation of the sodium/myo-inositol cotransporter in astrocyte cultures from different regions of the rat brain. Neuropharmacology 39:680–690Google Scholar
  181. Luse DS (2014) The RNA polymerase II preinitiation complex. Through what pathway is the complex assembled? Transcription 5:e27050Google Scholar
  182. Machado-Vieira R, Manji HK, Zarate CA Jr (2009) The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord 11(Suppl 2):92–109Google Scholar
  183. Machado-Vieira R, Pivovarova NB, Stanika RI, Yuan P, Wang Y, Zhou R, Zarate CA Jr, Drevets WC, Brantner CA, Baum A, Laje G, McMahon FJ, Chen G, Du J, Manji HK, Andrews SB (2011) The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum calcium release in subjects with bipolar disorder. Biol Psychiatry 69:344–352Google Scholar
  184. Mansur RB, Brietzke E (2012) The “selfish brain” hypothesis for metabolic abnormalities in bipolar disorder and schizophrenia. Trends Psychiatry Psychother 34:121–128Google Scholar
  185. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ (2010) The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 25:544–551Google Scholar
  186. Marin TL, Gongol B, Zhang F, Martin M, Johnson DA, Xiao H, Wang Y, Subramaniam S, Chien S, Shyy JY (2017) AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1. Sci Signal 10:eaaf7478Google Scholar
  187. Martinowich K, Schloesser RJ, Manji HK (2009) Bipolar disorder: from genes to behavior pathways. J Clin Invest 119:726–736Google Scholar
  188. Masuda CA, Xavier MA, Mattos KA, Galina A, Montero-Lomeli M (2001) Phosphoglucomutase is an in vivo lithium target in yeast. J Biol Chem 276:37794–37801Google Scholar
  189. Matskevitch J, Wagner CA, Risler T, Kwon HM, Handler JS, Waldegger S, Busch AE, Lang F (1998) Effect of extracellular pH on the myo-inositol transporter SMIT expressed in Xenopus oocytes. Pflugers Arch 436:854–857Google Scholar
  190. Maurer IC, Schippel P, Volz HP (2009) Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue. Bipolar Disord 11:515–522Google Scholar
  191. Mellor J, Morillon A (2004) ISWI complexes in Saccharomyces cerevisiae. Biochim Biophys Acta 1677:100–112Google Scholar
  192. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, Fullgrabe J, Jackson A, Jimenez Sanchez M, Karabiyik C, Licitra F, Lopez Ramirez A, Pavel M, Puri C, Renna M, Ricketts T, Schlotawa L, Vicinanza M, Won H, Zhu Y, Skidmore J, Rubinsztein DC (2017) Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93:1015–1034Google Scholar
  193. Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, Viana MC, Andrade LH, Hu C, Karam EG, Ladea M, Medina-Mora ME, Ono Y, Posada-Villa J, Sagar R, Wells JE, Zarkov Z (2011) Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry 68:241–251Google Scholar
  194. Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, Zheng Y, Diffenderfer KE, Zhang J, Soltani S, Eames T, Schafer ST, Boyer L, Marchetto MC, Nurnberger JI, Calabrese JR, Odegaard KJ, McCarthy MJ, Zandi PP, Alda M, Nievergelt CM, The Pharmacogenomics of Bipolar Disorder Study, Mi S, Brennand KJ, Kelsoe JR, Gage FH, Yao J (2015) Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527:95–99Google Scholar
  195. Mitchell PB, Malhi GS (2002) The expanding pharmacopoeia for bipolar disorder. Annu Rev Med 53:173–188Google Scholar
  196. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075Google Scholar
  197. Modica-Napolitano JS, Renshaw PF (2004) Ethanolamine and phosphoethanolamine inhibit mitochondrial function in vitro: implications for mitochondrial dysfunction hypothesis in depression and bipolar disorder. Biol Psychiatry 55:273–277Google Scholar
  198. Monastra G, Unfer V, Harrath AH, Bizzarri M (2017) Combining treatment with myo-inositol and D-chiro-inositol (40:1) is effective in restoring ovary function and metabolic balance in PCOS patients. Gynecol Endocrinol 33:1–9Google Scholar
  199. Moore CM, Breeze JL, Kukes TJ, Rose SL, Dager SR, Cohen BM, Renshaw PF (1999) Effects of myo-inositol ingestion on human brain myo-inositol levels: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatry 45:1197–1202Google Scholar
  200. Mori K (2009) Signalling pathways in the unfolded protein response: development from yeast to mammals. J Biochem 146:743–750Google Scholar
  201. Mukai T, Kishi T, Matsuda Y, Iwata N (2014) A meta-analysis of inositol for depression and anxiety disorders. Hum Psychopharmacol 29:55–63Google Scholar
  202. Munoz-Montano JR, Moreno FJ, Avila J, Diaz-Nido J (1997) Lithium inhibits Alzheimer’s disease-like tau protein phosphorylation in neurons. FEBS Lett 411:183–188Google Scholar
  203. Murashita J, Kato T, Shioiri T, Inubushi T, Kato N (2000) Altered brain energy metabolism in lithium-resistant bipolar disorder detected by photic stimulated 31P-MR spectroscopy. Psychol Med 30:107–115Google Scholar
  204. Nandhu MS, Paul J, Kuruvilla KP, Malat A, Romeo C, Paulose CS (2011) Enhanced glutamate, IP3 and cAMP activity in the cerebral cortex of unilateral 6-hydroxydopamine induced Parkinson’s rats: effect of 5-HT, GABA and bone marrow cell supplementation. J Biomed Sci 18:5Google Scholar
  205. Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G (1999) Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med 340:1314–1320Google Scholar
  206. Ng F, Hallam K, Lucas N, Berk M (2007) The role of lamotrigine in the management of bipolar disorder. Neuropsychiatr Dis Treat 3:463–474Google Scholar
  207. Nikawa J, Murakami A, Esumi E, Hosaka K (1995) Cloning and sequence of the SCS2 gene, which can suppress the defect of INO1 expression in an inositol auxotrophic mutant of Saccharomyces cerevisiae. J Biochem 118:39–45Google Scholar
  208. Nikoloff DM, Henry SA (1994) Functional characterization of the INO2 gene of Saccharomyces cerevisiae. A positive regulator of phospholipid biosynthesis. J Biol Chem 269:7402–7411Google Scholar
  209. Nikoloff DM, McGraw P, Henry SA (1992) The INO2 gene of Saccharomyces cerevisiae encodes a helix-loop-helix protein that is required for activation of phospholipid synthesis. Nucleic Acids Res 20:3253Google Scholar
  210. Nordio M, Proietti E (2012) The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. Eur Rev Med Pharmacol Sci 16:575–581Google Scholar
  211. O’Brien WT, Harper AD, Jove F, Woodgett JR, Maretto S, Piccolo S, Klein PS (2004) Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 24:6791–6798Google Scholar
  212. Orio F, Palomba S (2014) Reproductive endocrinology: new guidelines for the diagnosis and treatment of PCOS. Nat Rev Endocrinol 10:130–132Google Scholar
  213. Ortmeyer HK, Bodkin NL, Lilley K, Larner J, Hansen BC (1993) Chiroinositol deficiency and insulin resistance. I. Urinary excretion rate of chiroinositol is directly associated with insulin resistance in spontaneously diabetic rhesus monkeys. Endocrinology 132:640–645Google Scholar
  214. Pak Y, Hong Y, Kim S, Piccariello T, Farese RV, Larner J (1998) In vivo chiro-inositol metabolism in the rat: a defect in chiro-inositol synthesis from myo-inositol and an increased incorporation of chiro-[3H]inositol into phospholipid in the Goto-Kakizaki (G.K) rat. Mol Cells 8:301–309Google Scholar
  215. Papaleo E, Unfer V, Baillargeon JP, De Santis L, Fusi F, Brigante C, Marelli G, Cino I, Redaelli A, Ferrari A (2007) Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction. Gynecol Endocrinol 23:700–703Google Scholar
  216. Papaleo E, Unfer V, Baillargeon JP, Fusi F, Occhi F, De Santis L (2009) Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. Fertil Steril 91:1750–1754Google Scholar
  217. Parthasarathy RN, Lakshmanan J, Thangavel M, Seelan RS, Stagner JI, Janckila AJ, Vadnal RE, Casanova MF, Parthasarathy LK (2013) Rat brain myo-inositol 3-phosphate synthase is a phosphoprotein. Mol Cell Biochem 378:83–89Google Scholar
  218. Peterson CL, Kruger W, Herskowitz I (1991) A functional interaction between the C-terminal domain of RNA polymerase II and the negative regulator SIN1. Cell 64:1135–1143Google Scholar
  219. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741Google Scholar
  220. Piatkevich MM, Lisakovich MV, Efimov LA (1984) Method of identifying persons by their skulls using the photomatching technic. Sud Med Ekspert 27:31–33Google Scholar
  221. Pollard KJ, Peterson CL (1997) Role for ADA/GCN5 products in antagonizing chromatin-mediated transcriptional repression. Mol Cell Biol 17:6212–6222Google Scholar
  222. Ponchaut S, van Hoof F, Veitch K (1992) Cytochrome aa3 depletion is the cause of the deficient mitochondrial respiration induced by chronic valproate administration. Biochem Pharmacol 43:644–647Google Scholar
  223. Popkie AP, Zeidner LC, Albrecht AM, D’Ippolito A, Eckardt S, Newsom DE, Groden J, Doble BW, Aronow B, McLaughlin KJ, White P, Phiel CJ (2010) Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci. J Biol Chem 285:41337–41347Google Scholar
  224. Preston AS, Yamauchi A, Kwon HM, Handler JS (1995) Activators of protein kinase A and of protein kinase C inhibit MDCK cell myo-inositol and betaine uptake. J Am Soc Nephrol 6:1559–1564Google Scholar
  225. Qiu Y, Hassaninasab A, Han G-S, Carman GM (2016) Phosphorylation of Dgk1 diacylglycerol kinase by casein kinase II regulates phosphatidic acid production in Saccharomyces cerevisiae. J Biol Chem 291:26455–26467Google Scholar
  226. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529Google Scholar
  227. Rowe MK, Wiest C, Chuang DM (2007) GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder. Neurosci Biobehav Rev 31:920–931Google Scholar
  228. Rundlett SE, Carmen AA, Suka N, Turner BM, Grunstein M (1998) Transcriptional repression by UME6 involves deacetylation of lysine 5 of histone H4 by RPD3. Nature 392:831–835Google Scholar
  229. Salsaa M, Case K, Greenberg ML (2017) Orchestrating phospholipid biosynthesis: phosphatidic acid conducts and Opi1p performs. J Biol Chem 292:18729–18730Google Scholar
  230. Sarkar S, Rubinsztein DC (2006) Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations. Autophagy 2:132–134Google Scholar
  231. Sarkar S, Floto RA, Berger Z, Imarisio S, Cordenier A, Pasco M, Cook LJ, Rubinsztein DC (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170:1101–1111Google Scholar
  232. Saveanu R, Etkin A, Duchemin AM, Goldstein-Piekarski A, Gyurak A, Debattista C, Schatzberg AF, Sood S, Day CV, Palmer DM, Rekshan WR, Gordon E, Rush AJ, Williams LM (2015) The international Study to Predict Optimized Treatment in Depression (iSPOT-D): outcomes from the acute phase of antidepressant treatment. J Psychiatr Res 61:1–12Google Scholar
  233. Scheuing L, Chiu CT, Liao HM, Linares GR, Chuang DM (2014) Preclinical and clinical investigations of mood stabilizers for Huntington’s disease: what have we learned? Int J Biol Sci 10:1024–1038Google Scholar
  234. Schiebler M, Brown K, Hegyi K, Newton SM, Renna M, Hepburn L, Klapholz C, Coulter S, Obregon-Henao A, Henao Tamayo M, Basaraba R, Kampmann B, Henry KM, Burgon J, Renshaw SA, Fleming A, Kay RR, Anderson KE, Hawkins PT, Ordway DJ, Rubinsztein DC, Floto RA (2015) Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. EMBO Mol Med 7:127–139Google Scholar
  235. Schwank S, Ebbert R, Rautenstrauss K, Schweizer E, Schuller HJ (1995) Yeast transcriptional activator INO2 interacts as an Ino2p/Ino4p basic helix-loop-helix heteromeric complex with the inositol/choline-responsive element necessary for expression of phospholipid biosynthetic genes in Saccharomyces cerevisiae. Nucleic Acids Res 23:230–237Google Scholar
  236. Schwank S, Hoffmann B, Sch-uller HJ (1997) Influence of gene dosage and autoregulation of the regulatory genes INO2 and INO4 on inositol/choline-repressible gene transcription in the yeast Saccharomyces cerevisiae. Curr Genet 31:462–468Google Scholar
  237. Shaldubina A, Johanson RA, O'Brien WT, Buccafusca R, Agam G, Belmaker RH, Klein PS, Bersudsky Y, Berry GT (2006) SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior. Mol Genet Metab 88:384–388Google Scholar
  238. Shaldubina A, Buccafusca R, Johanson RA, Agam G, Belmaker RH, Berry GT, Bersudsky Y (2007) Behavioural phenotyping of sodium-myo-inositol cotransporter heterozygous knockout mice with reduced brain inositol. Genes Brain Behav 6:253–259Google Scholar
  239. Shao L, Sun X, Xu L, Young LT, Wang JF (2006) Mood stabilizing drug lithium increases expression of endoplasmic reticulum stress proteins in primary cultured rat cerebral cortical cells. Life Sci 78:1317–1323Google Scholar
  240. Shapiro J, Belmaker RH, Biegon A, Seker A, Agam G (2000) Scyllo-inositol in post-mortem brain of bipolar, unipolar and schizophrenic patients. J Neural Transm (Vienna) 107:603–607Google Scholar
  241. Shears SB (2009) Diphosphoinositol polyphosphates: metabolic messengers? Mol Pharmacol 76:236–252Google Scholar
  242. Shears SB (2015) Inositol pyrophosphates: why so many phosphates? Adv Biol Regul 57:203–216Google Scholar
  243. Shetty A, Lopes JM (2010) Derepression of INO1 transcription requires cooperation between the Ino2p-Ino4p heterodimer and Cbf1p and recruitment of the ISW2 chromatin-remodeling complex. Eukaryot Cell 9:1845–1855Google Scholar
  244. Shi Y, Azab AN, Thompson MN, Greenberg ML (2006) Inositol phosphates and phosphoinositides in health and disease. Subcell Biochem 39:265–292Google Scholar
  245. Shimon H, Agam G, Belmaker RH, Hyde TM, Kleinman JE (1997) Reduced frontal cortex inositol levels in postmortem brain of suicide victims and patients with bipolar disorder. Am J Psychiatry 154:1148–1150Google Scholar
  246. Shirra MK, Patton-Vogt J, Ulrich A, Liuta-Tehlivets O, Kohlwein SD, Henry SA, Arndt KM (2001) Inhibition of acetyl coenzyme A carboxylase activity restores expression of the INO1 gene in a snf1 mutant strain of Saccharomyces cerevisiae. Mol Cell Biol 21:5710–5722Google Scholar
  247. Shirra MK, Rogers SE, Alexander DE, Arndt KM (2005) The Snf1 protein kinase and Sit4 protein phosphatase have opposing functions in regulating TATA-binding protein association with the Saccharomyces cerevisiae INO1 promoter. Genetics 169:1957–1972Google Scholar
  248. Shorter E (2009) The history of lithium therapy. Bipolar Disord 11(Suppl 2):4–9Google Scholar
  249. Silva MF, Aires CC, Luis PB, Ruiter JP, IJlst L, Duran M, Wanders RJ, de Almeida IT (2008) Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inherit Metab Dis 31:205–216Google Scholar
  250. Silverstone PH, Wu RH, O’Donnell T, Ulrich M, Asghar SJ, Hanstock CC (2002) Chronic treatment with both lithium and sodium valproate may normalize phosphoinositol cycle activity in bipolar patients. Hum Psychopharmacol 17:321–327Google Scholar
  251. Simonsen A, Wurmser AE, Emr SD, Stenmark H (2001) The role of phosphoinositides in membrane transport. Curr Opin Cell Biol 13:485–492Google Scholar
  252. Singh N, Halliday AC, Thomas JM, Kuznetsova OV, Baldwin R, Woon EC, Aley PK, Antoniadou I, Sharp T, Vasudevan SR, Churchill GC (2013) A safe lithium mimetic for bipolar disorder. Nat Commun 4:1332Google Scholar
  253. Sitarz KS, Elliott HR, Karaman BS, Relton C, Chinnery PF, Horvath R (2014) Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts. Mol Genet Metab 112:57–63Google Scholar
  254. Slekar KH, Henry SA (1995) SIN3 works through two different promoter elements to regulate INO1 gene expression in yeast. Nucleic Acids Res 23:1964–1969Google Scholar
  255. So J, Warsh JJ, Li PP (2007) Impaired endoplasmic reticulum stress response in B-lymphoblasts from patients with bipolar-I disorder. Biol Psychiatry 62:141–147Google Scholar
  256. Soeiro-de-Souza MG, Dias VV, Figueira ML, Forlenza OV, Gattaz WF, Zarate CA Jr, Machado-Vieira R (2012) Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder. Acta Psychiatr Scand 126:332–341Google Scholar
  257. Song D, Du T, Li B, Cai L, Gu L, Li H, Chen Y, Hertz L, Peng L (2008) Astrocytic alkalinization by therapeutically relevant lithium concentrations: implications for myo-inositol depletion. Psychopharmacology 200:187–195Google Scholar
  258. Spector R (1976) Inositol accumulation by brain slices in vitro. J Neurochem 27:1273–1276Google Scholar
  259. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840Google Scholar
  260. Sreenivas A, Villa-Garcia MJ, Henry SA, Carman GM (2001) Phosphorylation of the yeast phospholipid synthesis regulatory protein Opi1p by protein kinase C. J Biol Chem 276:29915–29923Google Scholar
  261. Stambolic V, Ruel L, Woodgett JR (1996) Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol 6:1664–1668Google Scholar
  262. Stokes CE, Hawthorne JN (1987) Reduced phosphoinositide concentrations in anterior temporal cortex of Alzheimer-diseased brains. J Neurochem 48:1018–1021Google Scholar
  263. Stokes CE, Gillon KR, Hawthorne JN (1983) Free and total lipid myo-inositol concentrations decrease with age in human brain. Biochim Biophys Acta 753:136–138Google Scholar
  264. Stork C, Renshaw PF (2005) Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry 10:900–919Google Scholar
  265. Strange K (1992) Regulation of solute and water balance and cell volume in the central nervous system. J Am Soc Nephrol 3:12–27Google Scholar
  266. Strange K, Morrison R, Heilig CW, DiPietro S, Gullans SR (1991) Upregulation of inositol transport mediates inositol accumulation in hyperosmolar brain cells. Am J Phys 260:C784–C790Google Scholar
  267. Struewing IT, Barnett CD, Tang T, Mao CD (2007) Lithium increases PGC-1alpha expression and mitochondrial biogenesis in primary bovine aortic endothelial cells. FEBS J 274:2749–2765Google Scholar
  268. Sun TH, Heimark DB, Nguygen T, Nadler JL, Larner J (2002) Both myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to Wistar controls. Biochem Biophys Res Commun 293:1092–1098Google Scholar
  269. Sveinbjornsdottir S (2016) The clinical symptoms of Parkinson’s disease. J Neurochem 139(Suppl 1):318–324Google Scholar
  270. Szijgyarto Z, Garedew A, Azevedo C, Saiardi A (2011) Influence of inositol pyrophosphates on cellular energy dynamics. Science 334:802–805Google Scholar
  271. Tamaru H, Selker EU (2001) A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414:277–283Google Scholar
  272. Tamaru H, Zhang X, McMillen D, Singh PB, Nakayama J, Grewal SI, Allis CD, Cheng X, Selker EU (2003) Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurospora crassa. Nat Genet 34:75–79Google Scholar
  273. Tang TS, Tu H, Chan EY, Maximov A, Wang Z, Wellington CL, Hayden MR, Bezprozvanny I (2003) Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron 39:227–239Google Scholar
  274. Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, Llinas R, Kristal BS, Hayden MR, Bezprozvanny I (2005) Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington’s disease. Proc Natl Acad Sci U S A 102:2602–2607Google Scholar
  275. Tang TS, Guo C, Wang H, Chen X, Bezprozvanny I (2009) Neuroprotective effects of inositol 1,4,5-trisphosphate receptor C-terminal fragment in a Huntington’s disease mouse model. J Neurosci 29:1257–1266Google Scholar
  276. Tarasov AI, Griffiths EJ, Rutter GA (2012) Regulation of ATP production by mitochondrial Ca(2+). Cell Calcium 52:28–35Google Scholar
  277. Thomas MP, Mills SJ, Potter BV (2016) The “other” inositols and their phosphates: synthesis, biology, and medicine (with recent advances in myo-inositol chemistry). Angew Chem Int Ed Engl 55:1614–1650Google Scholar
  278. Toker A (2002) Phosphoinositides and signal transduction. Cell Mol Life Sci 59:761–779Google Scholar
  279. Toker L, Agam G (2015) Mitochondrial dysfunction in psychiatric morbidity: current evidence and therapeutic prospects. Neuropsychiatr Dis Treat 11:2441–2447Google Scholar
  280. Uldry M, Ibberson M, Horisberger JD, Chatton JY, Riederer BM, Thorens B (2001) Identification of a mammalian H(+)-myo-inositol symporter expressed predominantly in the brain. EMBO J 20:4467–4477Google Scholar
  281. Unfer V, Carlomagno G, Dante G, Facchinetti F (2012) Effects of myo-inositol in women with PCOS: a systematic review of randomized controlled trials. Gynecol Endocrinol 28:509–515Google Scholar
  282. Vaden DL, Ding D, Peterson B, Greenberg ML (2001) Lithium and valproate decrease inositol mass and increase expression of the yeast INO1 and INO2 genes for inositol biosynthesis. J Biol Chem 276:15466–15471Google Scholar
  283. Valvezan AJ, Klein PS (2012) GSK-3 and Wnt signaling in neurogenesis and bipolar disorder. Front Mol Neurosci 5:1Google Scholar
  284. Wagner C, Blank M, Strohmann B, Schuller HJ (1999) Overproduction of the Opi1 repressor inhibits transcriptional activation of structural genes required for phospholipid biosynthesis in the yeast Saccharomyces cerevisiae. Yeast 15:843–854Google Scholar
  285. Wagner C, Dietz M, Wittmann J, Albrecht A, Schuller HJ (2001) The negative regulator Opi1 of phospholipid biosynthesis in yeast contacts the pleiotropic repressor Sin3 and the transcriptional activator Ino2. Mol Microbiol 41:155–166Google Scholar
  286. Walker FO (2007) Huntington’s disease. Semin Neurol 27:143–150Google Scholar
  287. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086Google Scholar
  288. Warby SC, Graham RK, Hayden MR (1993) Huntington disease. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N (eds) GeneReviews(R). University of Washington, SeattleGoogle Scholar
  289. Weaver R (2012) Molecular biology. McGraw-Hill, New YorkGoogle Scholar
  290. White MJ, Hirsch JP, Henry SA (1991) The OPI1 gene of Saccharomyces cerevisiae, a negative regulator of phospholipid biosynthesis, encodes a protein containing polyglutamine tracts and a leucine zipper. J Biol Chem 266:863–872Google Scholar
  291. Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJ, Vos T (2013) Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382:1575–1586Google Scholar
  292. Whiting PH, Palmano KP, Hawthorne JN (1979) Enzymes of myo-inositol and inositol lipid metabolism in rats with streptozotocin-induced diabetes. Biochem J 179:549–553Google Scholar
  293. Williams RS, Cheng L, Mudge AW, Harwood AJ (2002) A common mechanism of action for three mood-stabilizing drugs. Nature 417:292–295Google Scholar
  294. Wilson MS, Livermore TM, Saiardi A (2013) Inositol pyrophosphates: between signalling and metabolism. Biochem J 452:369–379Google Scholar
  295. Wolfson M, Bersudsky Y, Zinger E, Simkin M, Belmaker RH, Hertz L (2000) 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 855:158–161Google Scholar
  296. Yadon AN, Singh BN, Hampsey M, Tsukiyama T (2013) DNA looping facilitates targeting of a chromatin remodeling enzyme. Mol Cell 50:93–103Google Scholar
  297. Yancey PH (2005) Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses. J Exp Biol 208:2819–2830Google Scholar
  298. Ye C, Greenberg ML (2015) Inositol synthesis regulates the activation of GSK-3alpha in neuronal cells. J Neurochem 133:273–283Google Scholar
  299. Ye C, Bandara WM, Greenberg ML (2013) Regulation of inositol metabolism is fine-tuned by inositol pyrophosphates in Saccharomyces cerevisiae. J Biol Chem 288:24898–24908Google Scholar
  300. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891Google Scholar
  301. Yu W, Greenberg ML (2016) Inositol depletion, GSK3 inhibition and bipolar disorder. Future Neurol 11:135–148Google Scholar
  302. Yu W, Ye C, Greenberg ML (2016) Inositol hexakisphosphate kinase 1 (IP6K1) regulates inositol synthesis in mammalian cells. J Biol Chem 291:10437–10444Google Scholar
  303. Yu W, Daniel J, Mehta D, Maddipati KR, Greenberg ML (2017) MCK1 is a novel regulator of myo-inositol phosphate synthase (MIPS) that is required for inhibition of inositol synthesis by the mood stabilizer valproate. PLoS One 12:e0182534Google Scholar
  304. Zheng H, Zhang L, Li L, Liu P, Gao J, Liu X, Zou J, Zhang Y, Liu J, Zhang Z, Li Z, Men W (2010) High-frequency rTMS treatment increases left prefrontal myo-inositol in young patients with treatment-resistant depression. Prog Neuro-Psychopharmacol Biol Psychiatry 34:1189–1195Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Kendall C. Case
    • 1
  • Michael Salsaa
    • 1
  • Wenxi Yu
    • 1
    • 2
  • Miriam L. Greenberg
    • 1
    Email author
  1. 1.Department of Biological SciencesWayne State UniversityDetroitUSA
  2. 2.Department of PharmacologyUniversity of Michigan Medical SchoolAnn ArborUSA

Personalised recommendations