The regulation of glutamic acid decarboxylases in GABA neurotransmission in the brain

  • Seong-Eun Lee
  • Yunjong Lee
  • Gum Hwa LeeEmail author


Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter that is required for the control of synaptic excitation/inhibition and neural oscillation. GABA is synthesized by glutamic acid decarboxylases (GADs) that are widely distributed and localized to axon terminals of inhibitory neurons as well as to the soma and, to a lesser extent, dendrites. The expression and activity of GADs is highly correlated with GABA levels and subsequent GABAergic neurotransmission at the inhibitory synapse. Dysregulation of GADs has been implicated in various neurological disorders including epilepsy and schizophrenia. Two isoforms of GADs, GAD67 and GAD65, are expressed from separate genes and have different regulatory processes and molecular properties. This review focuses on the recent advances in understanding the structure of GAD, its transcriptional regulation and post-transcriptional modifications in the central nervous system. This may provide insights into the pathological mechanisms underlying neurological diseases that are associated with GAD dysfunction.


Glutamic acid decarboxylase GABA Neurotransmission Inhibitory neuron Synaptic plasticity 



This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF2018R1D1A1B07043710).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. Ambrad Giovannetti E, Fuhrmann M (2019) Unsupervised excitation: GABAergic dysfunctions in Alzheimer’s disease. Brain Res 1707:216–226PubMedCrossRefGoogle Scholar
  2. Asada H, Kawamura Y, Maruyama K, Kume H, Ding R, Ji FY, Kanbara N, Kuzume H, Sanbo M, Yagi T, Obata K (1996) Mice lacking the 65 kDa isoform of glutamic acid decarboxylase (GAD65) maintain normal levels of GAD67 and GABA in their brains but are susceptible to seizures. Biochem Biophys Res Commun 229:891–895PubMedCrossRefGoogle Scholar
  3. Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, Kanbara N, Kuzume H, Sanbo M, Yagi T, Obata K (1997) Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 94:6496–6499PubMedCrossRefGoogle Scholar
  4. Baekkeskov S, Kanaani J (2009) Palmitoylation cycles and regulation of protein function (Review). Mol Membr Biol 26:42–54PubMedCrossRefGoogle Scholar
  5. Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P (1990) Identification of the 64 K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347:151–156PubMedCrossRefGoogle Scholar
  6. Bao J, Cheung WY, Wu JY (1995) Brain L-glutamate decarboxylase. Inhibition by phosphorylation and activation by dephosphorylation. J Biol Chem 270:6464–6467PubMedCrossRefGoogle Scholar
  7. Baptista MS, Melo CV, Armelao M, Herrmann D, Pimentel DO, Leal G, Caldeira MV, Bahr BA, Bengtson M, Almeida RD, Duarte CB (2010) Role of the proteasome in excitotoxicity-induced cleavage of glutamic acid decarboxylase in cultured hippocampal neurons. PLoS ONE 5:e10139PubMedPubMedCentralCrossRefGoogle Scholar
  8. Barker JL, Behar T, Li YX, Liu QY, Ma W, Maric D, Maric I, Schaffner AE, Serafini R, Smith SV, Somogyi R, Vautrin JY, Wen XL, Xian H (1998) GABAergic cells and signals in CNS development. Perspect Dev Neurobiol 5:305–322PubMedGoogle Scholar
  9. Battaglioli G, Liu H, Martin DL (2003) Kinetic differences between the isoforms of glutamate decarboxylase: implications for the regulation of GABA synthesis. J Neurochem 86:879–887PubMedCrossRefGoogle Scholar
  10. Baudry M, Bi X (2016) Calpain-1 and Calpain-2: the Yin and Yang of synaptic plasticity and neurodegeneration. Trends Neurosci 39:235–245PubMedPubMedCentralCrossRefGoogle Scholar
  11. Behar T, Schaffner A, Laing P, Hudson L, Komoly S, Barker J (1993) Many spinal cord cells transiently express low molecular weight forms of glutamic acid decarboxylase during embryonic development. Brain Res Dev Brain Res 72:203–218PubMedCrossRefGoogle Scholar
  12. Blaskovic S, Adibekian A, Blanc M, Van Der Goot GF (2014) Mechanistic effects of protein palmitoylation and the cellular consequences thereof. Chem Phys Lipids 180:44–52PubMedCrossRefGoogle Scholar
  13. Brown JA, Ramikie TS, Schmidt MJ, Baldi R, Garbett K, Everheart MG, Warren LE, Gellert L, Horvath S, Patel S, Mirnics K (2015) Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. Mol Psychiatry 20:1499–1507PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bu DF, Tobin AJ (1994) The exon-intron organization of the genes (GAD1 and GAD2) encoding two human glutamate decarboxylases (GAD67 and GAD65) suggests that they derive from a common ancestral GAD. Genomics 21:222–228PubMedCrossRefGoogle Scholar
  15. Bu DF, Erlander MG, Hitz BC, Tillakaratne NJ, Kaufman DL, Wagner-Mcpherson CB, Evans GA, Tobin AJ (1992) Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. Proc Natl Acad Sci USA 89:2115–2119PubMedCrossRefGoogle Scholar
  16. Buddhala C, Suarez M, Modi J, Prentice H, Ma Z, Tao R, Wu JY (2012) Calpain cleavage of brain glutamic acid decarboxylase 65 is pathological and impairs GABA neurotransmission. PLoS ONE 7:e33002PubMedPubMedCentralCrossRefGoogle Scholar
  17. Castren E, Zafra F, Thoenen H, Lindholm D (1992) Light regulates expression of brain-derived neurotrophic factor mRNA in rat visual cortex. Proc Natl Acad Sci USA 89:9444–9448PubMedCrossRefGoogle Scholar
  18. Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, Neul JL, Gong S, Lu HC, Heintz N, Ekker M, Rubenstein JL, Noebels JL, Rosenmund C, Zoghbi HY (2010) Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468:263–269PubMedPubMedCentralCrossRefGoogle Scholar
  19. Choi SY, Morales B, Lee HK, Kirkwood A (2002) Absence of long-term depression in the visual cortex of glutamic acid decarboxylase-65 knock-out mice. J Neurosci 22:5271–5276PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chou CC, Modi JP, Wang CY, Hsu PC, Lee YH, Huang KF, Wang AH, Nan C, Huang X, Prentice H, Wei J, Wu JY (2017) Activation of brain L-glutamate decarboxylase 65 isoform (GAD65) by phosphorylation at threonine 95 (T95). Mol Neurobiol 54:866–873PubMedCrossRefGoogle Scholar
  21. Christgau S, Schierbeck H, Aanstoot HJ, Aagaard L, Begley K, Kofod H, Hejnaes K, Baekkeskov S (1991) Pancreatic beta cells express two autoantigenic forms of glutamic acid decarboxylase, a 65-kDa hydrophilic form and a 64-kDa amphiphilic form which can be both membrane-bound and soluble. J Biol Chem 266:21257–21264PubMedGoogle Scholar
  22. Christgau S, Aanstoot HJ, Schierbeck H, Begley K, Tullin S, Hejnaes K, Baekkeskov S (1992) Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. J Cell Biol 118:309–320PubMedCrossRefGoogle Scholar
  23. Curley AA, Arion D, Volk DW, Asafu-Adjei JK, Sampson AR, Fish KN, Lewis DA (2011) Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features. Am J Psychiatry 168:921–929PubMedPubMedCentralCrossRefGoogle Scholar
  24. Dirkx R Jr, Thomas A, Li L, Lernmark A, Sherwin RS, De Camilli P, Solimena M (1995) Targeting of the 67-kDa isoform of glutamic acid decarboxylase to intracellular organelles is mediated by its interaction with the NH2-terminal region of the 65-kDa isoform of glutamic acid decarboxylase. J Biol Chem 270:2241–2246PubMedCrossRefGoogle Scholar
  25. Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ (1991) Two genes encode distinct glutamate decarboxylases. Neuron 7:91–100PubMedCrossRefGoogle Scholar
  26. Esclapez M, Tillakaratne NJ, Kaufman DL, Tobin AJ, Houser CR (1994) Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. J Neurosci 14:1834–1855PubMedPubMedCentralCrossRefGoogle Scholar
  27. Fenalti G, Law RH, Buckle AM, Langendorf C, Tuck K, Rosado CJ, Faux NG, Mahmood K, Hampe CS, Banga JP, Wilce M, Schmidberger J, Rossjohn J, El-Kabbani O, Pike RN, Smith AI, Mackay IR, Rowley MJ, Whisstock JC (2007) GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop. Nat Struct Mol Biol 14:280–286PubMedCrossRefGoogle Scholar
  28. Fujihara K, Miwa H, Kakizaki T, Kaneko R, Mikuni M, Tanahira C, Tamamaki N, Yanagawa Y (2015) Glutamate decarboxylase 67 deficiency in a subset of GABAergic neurons induces schizophrenia-related phenotypes. Neuropsychopharmacology 40:2475–2486PubMedPubMedCentralCrossRefGoogle Scholar
  29. Grattan DR, Rocca MS, Strauss KI, Sagrillo CA, Selmanoff M, Mccarthy MM (1996) GABAergic neuronal activity and mRNA levels for both forms of glutamic acid decarboxylase (GAD65 and GAD67) are reduced in the diagonal band of Broca during the afternoon of proestrus. Brain Res 733:46–55PubMedCrossRefGoogle Scholar
  30. Grayson DR, Guidotti A (2013) The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology 38:138–166PubMedCrossRefGoogle Scholar
  31. Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E (2000) Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 57:1061–1069PubMedCrossRefGoogle Scholar
  32. Hamazaki K, Maekawa M, Toyota T, Iwayama Y, Dean B, Hamazaki T, Yoshikawa T (2016) Fatty acid composition and fatty acid binding protein expression in the postmortem frontal cortex of patients with schizophrenia: a case-control study. Schizophr Res 171:225–232PubMedCrossRefGoogle Scholar
  33. Hanno-Iijima Y, Tanaka M, Iijima T (2015) Activity-dependent bidirectional regulation of gad expression in a homeostatic fashion is mediated by BDNF-dependent and independent pathways. PLoS ONE 10:e0134296PubMedPubMedCentralCrossRefGoogle Scholar
  34. Hashimoto T, Arion D, Unger T, Maldonado-Aviles JG, Morris HM, Volk DW, Mirnics K, Lewis DA (2008) Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 13:147–161PubMedCrossRefGoogle Scholar
  35. Heldt SA, Green A, Ressler KJ (2004) Prepulse inhibition deficits in GAD65 knockout mice and the effect of antipsychotic treatment. Neuropsychopharmacology 29:1610–1619PubMedCrossRefGoogle Scholar
  36. Hsu CC, Davis KM, Jin H, Foos T, Floor E, Chen W, Tyburski JB, Yang CY, Schloss JV, Wu JY (2000) Association of l-glutamic acid decarboxylase to the 70-kDa heat shock protein as a potential anchoring mechanism to synaptic vesicles. J Biol Chem 275:20822–20828PubMedCrossRefGoogle Scholar
  37. Huang HS, Akbarian S (2007) GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia. PLoS ONE 2:e809PubMedPubMedCentralCrossRefGoogle Scholar
  38. Huang K, Yanai A, Kang R, Arstikaitis P, Singaraja RR, Metzler M, Mullard A, Haigh B, Gauthier-Campbell C, Gutekunst CA, Hayden MR, El-Husseini A (2004) Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins. Neuron 44:977–986PubMedCrossRefGoogle Scholar
  39. Huang HS, Matevossian A, Whittle C, Kim SY, Schumacher A, Baker SP, Akbarian S (2007) Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. J Neurosci 27:11254–11262PubMedPubMedCentralCrossRefGoogle Scholar
  40. Huang K, Sanders S, Singaraja R, Orban P, Cijsouw T, Arstikaitis P, Yanai A, Hayden MR, El-Husseini A (2009) Neuronal palmitoyl acyl transferases exhibit distinct substrate specificity. FASEB J 23:2605–2615PubMedPubMedCentralCrossRefGoogle Scholar
  41. Hwang S, Ham S, Lee SE, Lee Y, Lee GH (2018) Hypoxia regulates the level of glutamic acid decarboxylase enzymes and interrupts inhibitory synapse stability in primary cultured neurons. Neurotoxicology 65:221–230PubMedCrossRefGoogle Scholar
  42. Ji F, Kanbara N, Obata K (1999) GABA and histogenesis in fetal and neonatal mouse brain lacking both the isoforms of glutamic acid decarboxylase. Neurosci Res 33:187–194PubMedCrossRefGoogle Scholar
  43. Jin H, Wu H, Osterhaus G, Wei J, Davis K, Sha D, Floor E, Hsu CC, Kopke RD, Wu JY (2003) Demonstration of functional coupling between gamma -aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles. Proc Natl Acad Sci USA 100:4293–4298PubMedCrossRefGoogle Scholar
  44. Jun HS, Khil LY, Yoon JW (2002) Role of glutamic acid decarboxylase in the pathogenesis of type 1 diabetes. Cell Mol Life Sci 59:1892–1901PubMedCrossRefGoogle Scholar
  45. Kaila K, Ruusuvuori E, Seja P, Voipio J, Puskarjov M (2014) GABA actions and ionic plasticity in epilepsy. Curr Opin Neurobiol 26:34–41PubMedCrossRefGoogle Scholar
  46. Kakizaki T, Oriuchi N, Yanagawa Y (2015) GAD65/GAD67 double knockout mice exhibit intermediate severity in both cleft palate and omphalocele compared with GAD67 knockout and VGAT knockout mice. Neuroscience 288:86–93PubMedCrossRefGoogle Scholar
  47. Kanaani J, Lissin D, Kash SF, Baekkeskov S (1999) The hydrophilic isoform of glutamate decarboxylase, GAD67, is targeted to membranes and nerve terminals independent of dimerization with the hydrophobic membrane-anchored isoform, GAD65. J Biol Chem 274:37200–37209PubMedCrossRefGoogle Scholar
  48. Kanaani J, El-Husseini Ael D, Aguilera-Moreno A, Diacovo JM, Bredt DS, Baekkeskov S (2002) A combination of three distinct trafficking signals mediates axonal targeting and presynaptic clustering of GAD65. J Cell Biol 158:1229–1238PubMedPubMedCentralCrossRefGoogle Scholar
  49. Kanaani J, Diacovo MJ, El-Husseini Ael D, Bredt DS, Baekkeskov S (2004) Palmitoylation controls trafficking of GAD65 from Golgi membranes to axon-specific endosomes and a Rab5a-dependent pathway to presynaptic clusters. J Cell Sci 117:2001–2013PubMedCrossRefGoogle Scholar
  50. Kanaani J, Patterson G, Schaufele F, Lippincott-Schwartz J, Baekkeskov S (2008) A palmitoylation cycle dynamically regulates partitioning of the GABA-synthesizing enzyme GAD65 between ER-Golgi and post-Golgi membranes. J Cell Sci 121:437–449PubMedCrossRefGoogle Scholar
  51. Kanaani J, Kolibachuk J, Martinez H, Baekkeskov S (2010) Two distinct mechanisms target GAD67 to vesicular pathways and presynaptic clusters. J Cell Biol 190:911–925PubMedPubMedCentralCrossRefGoogle Scholar
  52. Karolewicz B, Maciag D, O’dwyer G, Stockmeier CA, Feyissa AM, Rajkowska G (2010) Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol 13:411–420PubMedCrossRefGoogle Scholar
  53. Kash SF, Johnson RS, Tecott LH, Noebels JL, Mayfield RD, Hanahan D, Baekkeskov S (1997) Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 94:14060–14065PubMedCrossRefGoogle Scholar
  54. Kaufman DL, Houser CR, Tobin AJ (1991) Two forms of the gamma-aminobutyric acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J Neurochem 56:720–723PubMedCrossRefGoogle Scholar
  55. Kromkamp M, Uylings HB, Smidt MP, Hellemons AJ, Burbach JP, Kahn RS (2003) Decreased thalamic expression of the homeobox gene DLX1 in psychosis. Arch Gen Psychiatry 60:869–874PubMedCrossRefGoogle Scholar
  56. Kuki T, Fujihara K, Miwa H, Tamamaki N, Yanagawa Y, Mushiake H (2015) Contribution of parvalbumin and somatostatin-expressing GABAergic neurons to slow oscillations and the balance in beta-gamma oscillations across cortical layers. Front Neural Circuits 9:6PubMedPubMedCentralCrossRefGoogle Scholar
  57. Kullmann DM, Moreau AW, Bakiri Y, Nicholson E (2012) Plasticity of inhibition. Neuron 75:951–962PubMedCrossRefGoogle Scholar
  58. Kwakowsky A, Schwirtlich M, Zhang Q, Eisenstat DD, Erdelyi F, Baranyi M, Katarova ZD, Szabo G (2007) GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: correlation with Dlx2 and Dlx5. Dev Dyn 236:3532–3544PubMedCrossRefGoogle Scholar
  59. Laprade N, Soghomonian JJ (1995) MK-801 decreases striatal and cortical GAD65 mRNA levels. NeuroReport 6:1885–1889PubMedCrossRefGoogle Scholar
  60. Lau CG, Murthy VN (2012) Activity-dependent regulation of inhibition via GAD67. J Neurosci 32:8521–8531PubMedPubMedCentralCrossRefGoogle Scholar
  61. Lazarus MS, Krishnan K, Huang ZJ (2015) GAD67 deficiency in parvalbumin interneurons produces deficits in inhibitory transmission and network disinhibition in mouse prefrontal cortex. Cereb Cortex 25:1290–1296PubMedCrossRefGoogle Scholar
  62. Le TN, Zhou QP, Cobos I, Zhang S, Zagozewski J, Japoni S, Vriend J, Parkinson T, Du G, Rubenstein JL, Eisenstat DD (2017) GABAergic interneuron differentiation in the basal forebrain is mediated through direct regulation of glutamic acid decarboxylase isoforms by Dlx homeobox transcription factors. J Neurosci 37:8816–8829PubMedPubMedCentralCrossRefGoogle Scholar
  63. Lisman J (2012) Excitation, inhibition, local oscillations, or large-scale loops: what causes the symptoms of schizophrenia? Curr Opin Neurobiol 22:537–544PubMedCrossRefGoogle Scholar
  64. Loturco JJ, Owens DF, Heath MJ, Davis MB, Kriegstein AR (1995) GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 15:1287–1298PubMedCrossRefGoogle Scholar
  65. Lujan R, Shigemoto R, Lopez-Bendito G (2005) Glutamate and GABA receptor signalling in the developing brain. Neuroscience 130:567–580PubMedCrossRefGoogle Scholar
  66. Martin DL, Rimvall K (1993) Regulation of gamma-aminobutyric acid synthesis in the brain. J Neurochem 60:395–407PubMedCrossRefGoogle Scholar
  67. Martin DL, Liu H, Martin SB, Wu SJ (2000) Structural features and regulatory properties of the brain glutamate decarboxylases. Neurochem Int 37:111–119PubMedCrossRefGoogle Scholar
  68. Mason GF, Martin DL, Martin SB, Manor D, Sibson NR, Patel A, Rothman DL, Behar KL (2001) Decrease in GABA synthesis rate in rat cortex following GABA-transaminase inhibition correlates with the decrease in GAD(67) protein. Brain Res 914:81–91PubMedCrossRefGoogle Scholar
  69. Milosevic L, Gramer R, Kim TH, Algarni M, Fasano A, Kalia SK, Hodaie M, Lozano AM, Popovic MR, Hutchison WD (2019) Modulation of inhibitory plasticity in basal ganglia output nuclei of patients with Parkinson’s disease. Neurobiol Dis 124:46–56PubMedCrossRefGoogle Scholar
  70. Mitchell AC, Jiang Y, Peter C, Akbarian S (2015) Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia. Schizophr Res 167:28–34PubMedCrossRefGoogle Scholar
  71. Miyata S, Kumagaya R, Kakizaki T, Fujihara K, Wakamatsu K, Yanagawa Y (2019) Loss of glutamate decarboxylase 67 in somatostatin-expressing neurons leads to anxiety-like behavior and alteration in the Akt/GSK3beta signaling pathway. Front Behav Neurosci 13:131PubMedPubMedCentralCrossRefGoogle Scholar
  72. Namchuk M, Lindsay L, Turck CW, Kanaani J, Baekkeskov S (1997) Phosphorylation of serine residues 3, 6, 10, and 13 distinguishes membrane anchored from soluble glutamic acid decarboxylase 65 and is restricted to glutamic acid decarboxylase 65alpha. J Biol Chem 272:1548–1557PubMedCrossRefGoogle Scholar
  73. Obata K, Fukuda T, Konishi S, Ji FY, Mitoma H, Kosaka T (1999) Synaptic localization of the 67,000 mol. wt isoform of glutamate decarboxylase and transmitter function of GABA in the mouse cerebellum lacking the 65,000 mol. wt isoform. Neuroscience 93:1475–1482PubMedCrossRefGoogle Scholar
  74. Patel AB, De Graaf RA, Martin DL, Battaglioli G, Behar KL (2006) Evidence that GAD65 mediates increased GABA synthesis during intense neuronal activity in vivo. J Neurochem 97:385–396PubMedCrossRefGoogle Scholar
  75. Pinal CS, Tobin AJ (1998) Uniqueness and redundancy in GABA production. Perspect Dev Neurobiol 5:109–118PubMedGoogle Scholar
  76. Qi J, Kim M, Sanchez R, Ziaee SM, Kohtz JD, Koh S (2018) Enhanced susceptibility to stress and seizures in GAD65 deficient mice. PLoS ONE 13:e0191794PubMedPubMedCentralCrossRefGoogle Scholar
  77. Represa A, Ben-Ari Y (2005) Trophic actions of GABA on neuronal development. Trends Neurosci 28:278–283PubMedCrossRefGoogle Scholar
  78. Rocco BR, Lewis DA, Fish KN (2016) Markedly lower glutamic acid decarboxylase 67 protein levels in a subset of boutons in schizophrenia. Biol Psychiatry 79:1006–1015PubMedCrossRefGoogle Scholar
  79. Rozycka A, Liguz-Lecznar M (2017) The space where aging acts: focus on the GABAergic synapse. Aging Cell 16:634–643PubMedPubMedCentralCrossRefGoogle Scholar
  80. Sanchez-Huertas C, Rico B (2011) CREB-dependent regulation of GAD65 transcription by BDNF/TrkB in cortical interneurons. Cereb Cortex 21:777–788PubMedCrossRefGoogle Scholar
  81. Sandhu KV, Lang D, Muller B, Nullmeier S, Yanagawa Y, Schwegler H, Stork O (2014) Glutamic acid decarboxylase 67 haplodeficiency impairs social behavior in mice. Genes Brain Behav 13:439–450PubMedCrossRefGoogle Scholar
  82. Schmidli RS, Faulkner-Jones BE, Harrison LC, James RF, Deaizpurua HJ (1996) Cytokine regulation of glutamate decarboxylase biosynthesis in isolated rat islets of Langerhans. Biochem J 317(Pt 3):713–719PubMedPubMedCentralCrossRefGoogle Scholar
  83. Sha D, Wei J, Wu H, Jin Y, Wu JY (2005) Molecular cloning, expression, purification, and characterization of shorter forms of human glutamic decarboxylase 67 in an E. coli expression system. Brain Res Mol Brain Res 136:255–261PubMedCrossRefGoogle Scholar
  84. Sha D, Jin Y, Wu H, Wei J, Lin CH, Lee YH, Buddhala C, Kuchay S, Chishti AH, Wu JY (2008) Role of mu-calpain in proteolytic cleavage of brain l-glutamic acid decarboxylase. Brain Res 1207:9–18PubMedPubMedCentralCrossRefGoogle Scholar
  85. Somogyi R, Wen X, Ma W, Barker JL (1995) Developmental kinetics of GAD family mRNAs parallel neurogenesis in the rat spinal cord. J Neurosci 15:2575–2591PubMedPubMedCentralCrossRefGoogle Scholar
  86. Stork O, Yamanaka H, Stork S, Kume N, Obata K (2003) Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant mice. Genes Brain Behav 2:65–70PubMedCrossRefGoogle Scholar
  87. Subburaju S, Coleman AJ, Ruzicka WB, Benes FM (2016) Toward dissecting the etiology of schizophrenia: HDAC1 and DAXX regulate GAD67 expression in an in vitro hippocampal GABA neuron model. Transl Psychiatry 6:e723PubMedPubMedCentralCrossRefGoogle Scholar
  88. Tian N, Petersen C, Kash S, Baekkeskov S, Copenhagen D, Nicoll R (1999) The role of the synthetic enzyme GAD65 in the control of neuronal gamma-aminobutyric acid release. Proc Natl Acad Sci USA 96:12911–12916PubMedCrossRefGoogle Scholar
  89. Trifonov S, Yamashita Y, Kase M, Maruyama M, Sugimoto T (2014) Glutamic acid decarboxylase 1 alternative splicing isoforms: characterization, expression and quantification in the mouse brain. BMC Neurosci 15:114PubMedPubMedCentralCrossRefGoogle Scholar
  90. Varju P, Katarova Z, Madarasz E, Szabo G (2001) GABA signalling during development: new data and old questions. Cell Tissue Res 305:239–246PubMedCrossRefGoogle Scholar
  91. Wei J, Wu JY (2008) Post-translational regulation of l-glutamic acid decarboxylase in the brain. Neurochem Res 33:1459–1465PubMedCrossRefGoogle Scholar
  92. Wei J, Jin Y, Wu H, Sha D, Wu JY (2003) Identification and functional analysis of truncated human glutamic acid decarboxylase 65. J Biomed Sci 10:617–624PubMedCrossRefGoogle Scholar
  93. Wei J, Davis KM, Wu H, Wu JY (2004) Protein phosphorylation of human brain glutamic acid decarboxylase (GAD)65 and GAD67 and its physiological implications. Biochemistry 43:6182–6189PubMedCrossRefGoogle Scholar
  94. Wei J, Lin CH, Wu H, Jin Y, Lee YH, Wu JY (2006) Activity-dependent cleavage of brain glutamic acid decarboxylase 65 by calpain. J Neurochem 98:1688–1695PubMedCrossRefGoogle Scholar
  95. Xu FL, Zhu CL, Wang XY (2006) Developmental changes of glutamate acid decarboxylase-67 in mouse brain after hypoxia ischemia. Neurosci Bull 22:47–51PubMedGoogle Scholar
  96. Yamamoto Y, Kida H, Kagawa Y, Yasumoto Y, Miyazaki H, Islam A, Ogata M, Yanagawa Y, Mitsushima D, Fukunaga K, Owada Y (2018) FABP3 in the anterior cingulate cortex modulates the methylation status of the glutamic acid decarboxylase67 promoter region. J Neurosci 38:10411–10423PubMedPubMedCentralCrossRefGoogle Scholar
  97. Yamashima T (2013) Reconsider Alzheimer’s disease by the ‘calpain-cathepsin hypothesis’–a perspective review. Prog Neurobiol 105:1–23PubMedCrossRefGoogle Scholar
  98. Zafra F, Lindholm D, Castren E, Hartikka J, Thoenen H (1992) Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. J Neurosci 12:4793–4799PubMedPubMedCentralCrossRefGoogle Scholar
  99. Zhubi A, Chen Y, Guidotti A, Grayson DR (2017) Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects. Int J Dev Neurosci 62:63–72PubMedPubMedCentralCrossRefGoogle Scholar

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© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.College of PharmacyChosun UniversityGwangjuSouth Korea
  2. 2.Division of Pharmacology, Department of Molecular Cell BiologySungkyunkwan University School of MedicineSuwonSouth Korea

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