The glutamate hypothesis of schizophrenia: Evidence from human brain tissue studies

Annals of the New York Academy of Sciences

Volumn 1338, Issue 1, 2015, Pages 38-57

  Hu, Wei ^a   Macdonald, Matthew L ^b   Elswick, Daniel E ^a   Sweet, Robert A ^b,c  

^a WEST VIRGINIA UNIVERSITY   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^c VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

Brain tissue; EAAT; Glutamate receptors; Glutamatergic neurons; Schizophrenia

Indexed keywords

AMPA RECEPTOR; EXCITATORY AMINO ACID TRANSPORTER 2; GLUTAMATE AMMONIA LIGASE; GLUTAMATE RECEPTOR; GLUTAMIC ACID; GLUTAMINASE; KAINIC ACID RECEPTOR; MESSENGER RNA; METABOTROPIC RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NEUROFILAMENT PROTEIN; NEUROLEPTIC AGENT; SYNAPTOPHYSIN; VESICULAR GLUTAMATE TRANSPORTER 1; VESICULAR GLUTAMATE TRANSPORTER 2;

AMINO ACID TRANSPORT; ARTICLE; BRAIN CORTEX; BRAIN NERVE CELL; BRAIN REGION; BRAIN TISSUE; CELL STRUCTURE; CEREBELLUM; DENDRITE; DENDRITIC SPINE; DENTATE GYRUS; ENTORHINAL CORTEX; FRONTAL CORTEX; GENE EXPRESSION; HIPPOCAMPUS; HUMAN; HYPOTHESIS; INFERIOR TEMPORAL GYRUS; INTERNEURON; MIDDLE TEMPORAL GYRUS; NERVE FIBER; NEUROTRANSMISSION; NONHUMAN; OCCIPITAL CORTEX; ORBITAL CORTEX; PARIETAL CORTEX; PREFRONTAL CORTEX; PRIMARY AUDITORY CORTEX; PROTEIN EXPRESSION; PROTEIN SYNTHESIS; PYRAMIDAL NERVE CELL; SCHIZOPHRENIA; SIGNAL TRANSDUCTION; STRIATE CORTEX; SUBICULUM; TEMPORAL CORTEX; TEMPORAL LOBE; THALAMUS; BRAIN; FEMALE; GENETICS; MALE; METABOLISM;

BRAIN; FEMALE; GLUTAMIC ACID; HUMANS; MALE; RECEPTORS, GLUTAMATE; RNA, MESSENGER; SCHIZOPHRENIA;

EID: 84924977090     PISSN: 00778923     EISSN: 17496632     Source Type: Journal    
DOI: 10.1111/nyas.12547     Document Type: Article

References (181)

1. Javitt, D.C. 1987. Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia Hillside. J. Clin. Psychiatry 9: 12-35.
2. Javitt, D.C. & S.R. Zukin . 1991. Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry 148: 1301-1308.
3. Olney, J.W. & N.B. Farber . 1995. Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psychiatry 52: 998-1007.
4. Coyle, J.T. 1996. The glutamatergic dysfunction hypothesis for schizophrenia. Harv. Rev. Psychiatry 3: 241-253.
5. Krystal, J.H., L.P. Karper, J.P. Seibyl, et al. 1994. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 51: 199-214.
6. Malhotra, A.K., D.A. Pinals, C.M. Adler, et al. 1997. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17: 141-150.
7. Javitt, D.C., S.R. Zukin, U. Heresco-Levy, et al. 2012. Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr. Bull. 38: 958-966.
8. Lipska, B.K. & D.R. Weinberger . 2000. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23: 223-239.
9. Dalmau, J., A.J. Gleichman, E.G. Hughes, et al. 2008. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7: 1091-1098.
10. Hughes, E.G., X. Peng, A.J. Gleichman, et al. 2010. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J. Neurosci. 30: 5866-5875.
11. Balu, D.T., Y. Li, M.D. Puhl, et al. 2013. Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc. Natl. Acad. Sci. USA 110: E2400-E2409.
12. Poels, E.M., L.S. Kegeles, J.T. Kantrowitz, et al. 2014. Glutamatergic abnormalities in schizophrenia: a review of proton MRS findings. Schizophr. Res. 152: 325-332.
13. Harrison, P.J. & D.R. Weinberger . 2005. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol. Psychiatry 10: 40-68.
14. Ripke, S., C. O'Dushlaine, K. Chambert, et al. 2013. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45: 1150-1159.
15. Fromer, M., A.J. Pocklington, D.H. Kavanagh, et al. 2014. De novo mutations in schizophrenia implicate synaptic networks. Nature 506: 179-184.
16. Purcell, S.M., J.L. Moran, M. Fromer, et al. 2014. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506: 185-190.
17. Pierri, J.N., C.L. Volk, S. Auh, et al. 2001. Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia. Arch. Gen. Psychiatry 58: 466-473.
18. Pierri, J.N., C.L. Volk, S. Auh, et al. 2003. Somal size of prefrontal cortical pyramidal neurons in schizophrenia: differential effects across neuronal subpopulations. Biol. Psychiatry 54: 111-120.
19. Rajkowska, G., L.D. Selemon & P.S. Goldman-Rakic . 1998. Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch. Gen. Psychiatry 55: 215-224.
20. Miguel-Hidalgo, J.J., P. Dubey, Q. Shao, et al. 2005. Unchanged packing density but altered size of neurofilament immunoreactive neurons in the prefrontal cortex in schizophrenia and major depression. Schizophr. Res. 76: 159-171.
21. Maldonado-Aviles, J.G., Q. Wu, A.R. Sampson, et al. 2006. Somal size of immunolabeled pyramidal cells in the prefrontal cortex of subjects with schizophrenia. Biol. Psychiatry 60: 226-234.
22. Sweet, R.A., J.N. Pierri, S. Auh, et al. 2003. Reduced pyramidal cell somal volume in auditory association cortex of subjects with schizophrenia. Neuropsychopharmacology 28: 599-609.
23. Sweet, R.A., S.E. Bergen, Z. Sun, et al. 2004. Pyramidal cell size reduction in schizophrenia: evidence for involvement of auditory feedforward circuits. Biol. Psychiatry 55: 1128-1137.
24. Smiley, J.F., G. Rosoklija, B. Mancevski, et al. 2011. Hemispheric comparisons of neuron density in the planum temporale of schizophrenia and nonpsychiatric brains. Psychiatry Res. 192: 1-11.
25. Pennington, K., P. Dicker, L. Hudson, et al. 2008. Evidence for reduced neuronal somal size within the insular cortex in schizophrenia, but not in affective disorders. Schizophr. Res. 106: 164-171.
26. Di Rosa, E., T.J. Crow, M.A. Walker, et al. 2009. Reduced neuron density, enlarged minicolumn spacing and altered ageing effects in fusiform cortex in schizophrenia. Psychiatry Res. 166: 102-115.
27. Smiley, J.F., K. Konnova & C. Bleiwas . 2012. Cortical thickness, neuron density and size in the inferior parietal lobe in schizophrenia. Schizophr. Res. 136: 43-50.
28. Black, J.E., I.M. Kodish, A.W. Grossman, et al. 2004. Pathology of layer V pyramidal neurons in the prefrontal cortex of patients with schizophrenia. Am. J. Psychiatry 161: 742-744.
29. Broadbelt, K., W. Byne & L.B. Jones . 2002. Evidence for a decrease in basilar dendrites of pyramidal cells in schizophrenic medial prefrontal cortex. Schizophr. Res. 58: 75-81.
30. Kalus, P., T.J. Muller, W. Zuschratter, et al. 2000. The dendritic architecture of prefrontal pyramidal neurons in schizophrenic patients. Neuroreport 11: 3621-3625.
31. Glantz, L.A. & D.A. Lewis . 2000. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57: 65-73.
32. Kolluri, N., Z. Sun, A.R. Sampson, et al. 2005. Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. Am. J. Psychiatry 162: 1200-1202.
33. Garey, L.J., W.Y. Ong, T.S. Patel, et al. 1998. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J. Neurol. Neurosurg. Psychiatry 65: 446-453.
34. Rosoklija, G., G. Toomayan, S.P. Ellis, et al. 2000. Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings. Arch. Gen. Psychiatry 57: 349-356.
35. Sweet, R.A., R.A. Henteleff, W. Zhang, et al. 2009. Reduced dendritic spine density in auditory cortex of subjects with schizophrenia. Neuropsychopharmacology 34: 374-389.
36. Jahn, R., W. Schiebler, C. Ouimet, et al. 1985. A 38, 000-dalton membrane protein (p38) present in synaptic vesicles. Proc. Natl. Acad. Sci. USA 82: 4137-4141.
37. Navone, F., R. Jahn, G.G. Di, et al. 1986. Protein p38: an integral membrane protein specific for small vesicles of neurons and neuroendocrine cells. J. Cell Biol. 103: 2511-2527.
38. Wiedenmann, B. & W.W. Franke . 1985. Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38, 000 characteristic of presynaptic vesicles. Cell 41: 1017-1028.
39. Hamos, J.E., L.J. Degennaro & D.A. Drachman . 1989. Synaptic loss in Alzheimer's disease and other dementias. Neurology 39: 355-361.
40. Masliah, E., R.D. Terry, M. Alford, et al. 1990. Quantitative immunohistochemistry of synaptophysin in human neocortex: an alternative method to estimate density of presynaptic terminals in paraffin sections. J. Histochem. Cytochem. 38: 837-844.
41. Masliah, E., R.D. Terry, M. Alford, et al. 1991. Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer's disease. Am. J. Pathol. 138: 235-246.
42. Eastwood, S.L. & P.J. Harrison . 1995. Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography. Neuroscience 69: 339-343.
43. Glantz, L.A. & D.A. Lewis . 1997. Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity. Arch. Gen. Psychiatry 54: 943-952.
44. Karson, C.N., R.E. Mrak, K.O. Schluterman, et al. 1999. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for 'hypofrontality'. Mol. Psychiatry 4: 39-45.
45. Honer, W.G., P. Falkai, C. Chen, et al. 1999. Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness. Neuroscience 91: 1247-1255.
46. Davidsson, P., J. Gottfries, N. Bogdanovic, et al. 1999. The synaptic-vesicle-specific proteins rab3a and synaptophysin are reduced in thalamus and related cortical brain regions in schizophrenic brains. Schizophr. Res. 40: 23-29.
47. Perrone-Bizzozero, N.I., A.C. Sower, E.D. Bird, et al. 1996. Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. Proc. Natl. Acad. Sci. USA 93: 14182-14187.
48. Rao, J.S., H.W. Kim, G.J. Harry, et al. 2013. Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr. Res. 147: 24-31.
49. Eastwood, S.L., P.W. Burnet & P.J. Harrison . 1995. Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia. Neuroscience 66: 309-319.
50. Eastwood, S.L., N.J. Cairns & P.J. Harrison . 2000. Synaptophysin gene expression in schizophrenia. Investigation of synaptic pathology in the cerebral cortex. Br. J. Psychiatry 176: 236-242.
51. Eastwood, S.L. & P.J. Harrison . 2001. Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins. Brain Res. Bull. 55: 569-578.
52. Gabriel, S.M., V. Haroutunian, P. Powchik, et al. 1997. Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia. Arch. Gen. Psychiatry 54: 559-566.
53. Halim, N.D., C.S. Weickert, B.W. Mcclintock, et al. 2003. Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development. Mol. Psychiatry 8: 797-810.
54. Honer, W.G., P. Falkai, C. Young, et al. 1997. Cingulate cortex synaptic terminal proteins and neural cell adhesion molecule in schizophrenia. Neuroscience 78: 99-110.
55. Sweet, R.A., S.E. Bergen, Z. Sun, et al. 2007. Anatomical evidence of impaired feedforward auditory processing in schizophrenia. Biol. Psychiatry 61: 854-864.
56. Moyer, C.E., K.M. Delevich, K.N. Fish, et al. 2013. Intracortical excitatory and thalamocortical boutons are intact in primary auditory cortex in schizophrenia. Schizophr. Res. 149: 127-134.
57. Willard, S.S. & S. Koochekpour . 2013. Glutamate, glutamate receptors, and downstream signaling pathways. Int. J. Biol. Sci. 9: 948-959.
58. Collingridge, G.L., R.W. Olsen, J. Peters, et al. 2009. A nomenclature for ligand-gated ion channels. Neuropharmacology 56: 2-5.
59. Lerma, J. 2003. Roles and rules of kainate receptors in synaptic transmission. Nat. Rev. Neurosci. 4: 481-495.
60. Schoepp, D.D. 2001. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther. 299: 12-20.
61. Sequeira, P.A., M.V. Martin & M.P. Vawter . 2012. The first decade and beyond of transcriptional profiling in schizophrenia. Neurobiol. Dis. 45: 23-36.
62. Rubio, M.D., J.B. Drummond & J.H. Meador-Woodruff . 2012. Glutamate receptor abnormalities in schizophrenia: implications for innovative treatments. Biomol. Ther. (Seoul.) 20: 1-18.
63. Beneyto, M. & J.H. Meador-Woodruff . 2008. Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology 33: 2175-2186.
64. Sokolov, B.P. 1998. Expression of NMDAR1, GluR1, GluR7, and KA1 glutamate receptor mRNAs is decreased in frontal cortex of "neuroleptic-free" schizophrenics: evidence on reversible up-regulation by typical neuroleptics. J. Neurochem. 71: 2454-2464.
65. Weickert, C.S., S.J. Fung, V.S. Catts, et al. 2013. Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol. Psychiatry 18: 1185-1192.
66. Akbarian, S., N.J. Sucher, D. Bradley, et al. 1996. Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. J. Neurosci. 16: 19-30.
67. Dracheva, S., S.A. Marras, S.L. Elhakem, et al. 2001. N-methyl-D-aspartic acid receptor expression in the dorsolateral prefrontal cortex of elderly patients with schizophrenia. Am. J. Psychiatry 158: 1400-1410.
68. Le Corre, S., C.G. Harper, P. Lopez, et al. 2000. Increased levels of expression of an NMDARI splice variant in the superior temporal gyrus in schizophrenia. Neuroreport 11: 983-986.
69. Rao, J.S., M. Kellom, E.A. Reese, et al. 2012. Dysregulated glutamate and dopamine transporters in postmortem frontal cortex from bipolar and schizophrenic patients. J. Affect. Disord. 136: 63-71.
70. Mueller, H.T. & J.H. Meador-Woodruff . 2004. NR3A NMDA receptor subunit mRNA expression in schizophrenia, depression and bipolar disorder. Schizophr. Res. 71: 361-370.
71. Beneyto, M. & J.H. Meador-Woodruff . 2006. Lamina-specific abnormalities of AMPA receptor trafficking and signaling molecule transcripts in the prefrontal cortex in schizophrenia. Synapse 60: 585-598.
72. Dracheva, S., S.R. Mcgurk & V. Haroutunian . 2005. mRNA expression of AMPA receptors and AMPA receptor binding proteins in the cerebral cortex of elderly schizophrenics. J. Neurosci. Res. 79: 868-878.
73. Healy, D.J., V. Haroutunian, P. Powchik, et al. 1998. AMPA receptor binding and subunit mRNA expression in prefrontal cortex and striatum of elderly schizophrenics. Neuropsychopharmacology 19: 278-286.
74. Scarr, E., M. Beneyto, J.H. Meador-Woodruff, et al. 2005. Cortical glutamatergic markers in schizophrenia. Neuropsychopharmacology 30: 1521-1531.
75. Meador-Woodruff, J.H., K.L. Davis & V. Haroutunian . 2001. Abnormal kainate receptor expression in prefrontal cortex in schizophrenia. Neuropsychopharmacology 24: 545-552.
76. Volk, D.W., S.M. Eggan & D.A. Lewis . 2010. Alterations in metabotropic glutamate receptor 1alpha and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. Am. J. Psychiatry 167: 1489-1498.
77. Ohnuma, T., S.J. Augood, H. Arai, et al. 1998. Expression of the human excitatory amino acid transporter-2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. Brain Res. Mol. Brain Res. 56: 207-217.
78. Gonzalez-Maeso, J., R.L. Ang, T. Yuen, et al. 2008. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452: 93-97.
79. Ghose, S., J.M. Crook, C.L. Bartus, et al. 2008. Metabotropic glutamate receptor 2 and 3 gene expression in the human prefrontal cortex and mesencephalon in schizophrenia Int. J. Neurosci. 118: 1609-1627.
80. Humphries, C., A. Mortimer, S. Hirsch, et al. 1996. NMDA receptor mRNA correlation with antemortem cognitive impairment in schizophrenia. Neuroreport 7: 2051-2055.
81. Eastwood, S.L., B. Mcdonald, P.W. Burnet, et al. 1995. Decreased expression of mRNAs encoding non-NMDA glutamate receptors GluR1 and GluR2 in medial temporal lobe neurons in schizophrenia. Brain Res. Mol. Brain Res. 29: 211-223.
82. Beneyto, M., L.V. Kristiansen, A. Oni-Orisan, et al. 2007. Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 32: 1888-1902.
83. Eastwood, S.L., P.W. Burnet & P.J. Harrison . 1997. GluR2 glutamate receptor subunit flip and flop isoforms are decreased in the hippocampal formation in schizophrenia: a reverse transcriptase-polymerase chain reaction (RT-PCR) study. Brain Res. Mol. Brain Res. 44: 92-98.
84. Gao, X.M., K. Sakai, R.C. Roberts, et al. 2000. Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. Am. J. Psychiatry 157: 1141-1149.
85. Harrison, P.J., D. Mclaughlin & R.W. Kerwin . 1991. Decreased hippocampal expression of a glutamate receptor gene in schizophrenia. Lancet 337: 450-452.
86. Vrajova, M., F. Stastny, J. Horacek, et al. 2010. Expression of the hippocampal NMDA receptor GluN1 subunit and its splicing isoforms in schizophrenia: postmortem study. Neurochem. Res. 35: 994-1002.
87. Porter, R.H., S.L. Eastwood & P.J. Harrison . 1997. Distribution of kainate receptor subunit mRNAs in human hippocampus, neocortex and cerebellum, and bilateral reduction of hippocampal GluR6 and KA2 transcripts in schizophrenia. Brain Res. 751: 217-231.
88. Clinton, S.M., V. Haroutunian, K.L. Davis, et al. 2003. Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia. Am. J. Psychiatry 160: 1100-1109.
89. Ibrahim, H.M., A.J. Hogg, Jr., D.J. Healy, et al. 2000. Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia. Am. J. Psychiatry 157: 1811-1823.
90. Sodhi, M.S., M. Simmons, R. Mccullumsmith, et al. 2011. Glutamatergic gene expression is specifically reduced in thalamocortical projecting relay neurons in schizophrenia. Biol. Psychiatry 70: 646-654.
91. Clinton, S.M. & J.H. Meador-Woodruff . 2004. Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder. Neuropsychopharmacology 29: 1353-1362.
92. Dracheva, S., W. Byne, B. Chin, et al. 2008. Ionotropic glutamate receptor mRNA expression in the human thalamus: absence of change in schizophrenia. Brain Res. 1214: 23-34.
93. Richardson-Burns, S.M., V. Haroutunian, K.L. Davis, et al. 2000. Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus. Biol. Psychiatry 47: 22-28.
94. Kristiansen, L.V., M. Beneyto, V. Haroutunian, et al. 2006. Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia. Mol. Psychiatry 11: 737-47, 705.
95. + ATPase-α1 in the prefrontal cortex of subjects with schizophrenia. Schizophr. Res. 128: 7-14.
96. Crook, J.M., M. Akil, B.C. Law, et al. 2002. Comparative analysis of group II metabotropic glutamate receptor immunoreactivity in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects. Mol. Psychiatry 7: 157-164.
97. Gupta, D.S., R.E. Mccullumsmith, M. Beneyto, et al. 2005. Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia. Synapse 57: 123-131.
98. Ghose, S., K.A. Gleason, B.W. Potts, et al. 2009. Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: a mechanism for antipsychotic drug action?. Am. J. Psychiatry 166: 812-820.
99. Matosin, N., E. Frank, C. Deng, et al. 2013. Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment. Schizophr. Res. 146: 170-176.
100. MacDonald, M.L., Y. Ding, J. Newman, et al. 2014. Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia. Biol. Psychiatry. In press.
101. Fremeau, R.T., Jr., S. Voglmaier, R.P. Seal, et al. 2004. VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci. 27: 98-103.
102. Fremeau, R.T., Jr., M.D. Troyer, I. Pahner, et al. 2001. The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron 31: 247-260.
103. Fremeau, R.T., Jr., K. Kam, T. Qureshi, et al. 2004. Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science 304: 1815-1819.
104. Wilson, N.R., J. Kang, E.V. Hueske, et al. 2005. Presynaptic regulation of quantal size by the vesicular glutamate transporter VGLUT1. J. Neurosci. 25: 6221-6234.
105. Eastwood, S.L. & P.J. Harrison . 2005. Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons. Schizophr. Res. 73: 159-172.
106. Fung, S.J., S. Sivagnanasundaram & C.S. Weickert . 2011. Lack of change in markers of presynaptic terminal abundance alongside subtle reductions in markers of presynaptic terminal plasticity in prefrontal cortex of schizophrenia patients. Biol. Psychiatry 69: 71-79.
107. Oni-Orisan, A., L.V. Kristiansen, V. Haroutunian, et al. 2008. Altered vesicular glutamate transporter expression in the anterior cingulate cortex in schizophrenia. Biol. Psychiatry 63: 766-775.
108. Shan, D., E.K. Lucas, J.B. Drummond, et al. 2013. Abnormal expression of glutamate transporters in temporal lobe areas in elderly patients with schizophrenia. Schizophr. Res. 144: 1-8.
109. Uezato, A., J.H. Meador-Woodruff & R.E. Mccullumsmith . 2009. Vesicular glutamate transporter mRNA expression in the medial temporal lobe in major depressive disorder, bipolar disorder, and schizophrenia. Bipolar. Disord. 11: 711-725.
110. Talbot, K., W.L. Eidem, C.L. Tinsley, et al. 2004. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J. Clin. Invest 113: 1353-1363.
111. Amara, S.G. & A.C. Fontana . 2002. Excitatory amino acid transporters: keeping up with glutamate. Neurochem. Int. 41: 313-318.
112. Lauriat, T.L., S. Dracheva, B. Chin, et al. 2006. Quantitative analysis of glutamate transporter mRNA expression in prefrontal and primary visual cortex in normal and schizophrenic brain. Neuroscience 137: 843-851.
113. Sheldon, A.L. & M.B. Robinson . 2007. The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochem. Int. 51: 333-355.
114. Massie, A., F. Vandesande & L. Arckens . 2001. Expression of the high-affinity glutamate transporter EAAT4 in mammalian cerebral cortex. Neuroreport 12: 393-397.
115. +-dependent glutamate transporter EAAT4 is expressed throughout the rat fore- and midbrain. J. Comp Neurol. 511: 155-172.
116. Nieoullon, A., B. Canolle, F. Masmejean, et al. 2006. The neuronal excitatory amino acid transporter EAAC1/EAAT3: does it represent a major actor at the brain excitatory synapse? J. Neurochem. 98: 1007-1018.
117. Bar-Peled, O., H. Ben-Hur, A. Biegon, et al. 1997. Distribution of glutamate transporter subtypes during human brain development. J. Neurochem. 69: 2571-2580.
118. Robinson, M.B. 1998. The family of sodium-dependent glutamate transporters: a focus on the GLT-1/EAAT2 subtype. Neurochem. Int. 33: 479-491.
119. Bauer, D., D. Gupta, V. Harotunian, et al. 2008. Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia. Schizophr. Res. 104: 108-120.
120. Bauer, D., V. Haroutunian, J.H. Meador-Woodruff, et al. 2010. Abnormal glycosylation of EAAT1 and EAAT2 in prefrontal cortex of elderly patients with schizophrenia. Schizophr. Res. 117: 92-98.
121. Danbolt, N.C. 2001. Glutamate uptake. Prog. Neurobiol. 65: 1-105.
122. Rose, C.F., A. Verkhratsky & V. Parpura . 2013. Astrocyte glutamine synthetase: pivotal in health and disease. Biochem. Soc. Trans. 41: 1518-1524.
123. Katsel, P., W. Byne, P. Roussos, et al. 2011. Astrocyte and glutamate markers in the superficial, deep, and white matter layers of the anterior cingulate gyrus in schizophrenia. Neuropsychopharmacology 36: 1171-1177.
124. Steffek, A.E., R.E. Mccullumsmith, V. Haroutunian, et al. 2008. Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia. Schizophr. Res. 103: 71-82.
125. Burbaeva, G.S., I.S. Boksha, M.S. Turishcheva, et al. 2003. Glutamine synthetase and glutamate dehydrogenase in the prefrontal cortex of patients with schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 27: 675-680.
126. Prabakaran, S., J.E. Swatton, M.M. Ryan, et al. 2004. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol. Psychiatry 9: 684-697, 643.
127. Toro, C.T., J.E. Hallak, J.S. Dunham, et al. 2006. Glial fibrillary acidic protein and glutamine synthetase in subregions of prefrontal cortex in schizophrenia and mood disorder. Neurosci. Lett. 404: 276-281.
128. Martins-De-Souza, D., A. Schmitt, R. Roder, et al. 2010. Sex-specific proteome differences in the anterior cingulate cortex of schizophrenia. J. Psychiatr. Res. 44: 989-991.
129. Gluck, M.R., R.G. Thomas, K.L. Davis, et al. 2002. Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients. Am. J. Psychiatry 159: 1165-1173.
130. Bruneau, E.G., R.E. Mccullumsmith, V. Haroutunian, et al. 2005. Increased expression of glutaminase and glutamine synthetase mRNA in the thalamus in schizophrenia. Schizophr. Res. 75: 27-34.
131. Mothet, J.P., A.T. Parent, H. Wolosker, et al. 2000. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc. Natl. Acad. Sci. USA 97: 4926-4931.
132. De Miranda, J., R. Panizzutti, V.N. Foltyn, et al. 2002. Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine. Proc. Natl. Acad. Sci. USA 99: 14542-14547.
133. Wolosker, H., S. Blackshaw & S.H. Snyder . 1999. Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc. Natl. Acad. Sci. USA 96: 13409-13414.
134. Horiike, K., H. Tojo, R. Arai, et al. 1987. Localization of D-amino acid oxidase in Bergmann glial cells and astrocytes of rat cerebellum. Brain Res. Bull. 19: 587-596.
135. Schell, M.J., M.E. Molliver & S.H. Snyder . 1995. D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc. Natl. Acad. Sci. USA 92: 3948-3952.
136. Labrie, V., A.H. Wong & J.C. Roder . 2012. Contributions of the D-serine pathway to schizophrenia. Neuropharmacology 62: 1484-1503.
137. Bendikov, I., C. Nadri, S. Amar, et al. 2007. A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. Schizophr. Res. 90: 41-51.
138. Kapoor, R., K.S. Lim, A. Cheng, et al. 2006. Preliminary evidence for a link between schizophrenia and NMDA-glycine site receptor ligand metabolic enzymes, d-amino acid oxidase (DAAO) and kynurenine aminotransferase-1 (KAT-1). Brain Res. 1106: 205-210.
139. Steffek, A.E., V. Haroutunian & J.H. Meador-Woodruff . 2006. Serine racemase protein expression in cortex and hippocampus in schizophrenia. Neuroreport 17: 1181-1185.
140. Verrall, L., M. Walker, N. Rawlings, et al. 2007. d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia. Eur. J. Neurosci. 26: 1657-1669.
141. Moreno, S., R. Nardacci, A. Cimini, et al. 1999. Immunocytochemical localization of D-amino acid oxidase in rat brain. J. Neurocytol. 28: 169-185.
142. Ono, K., Y. Shishido, H.K. Park, et al. 2009. Potential pathophysiological role of D-amino acid oxidase in schizophrenia: immunohistochemical and in situ hybridization study of the expression in human and rat brain. J. Neural Transm. 116: 1335-1347.
143. Madeira, C., M.E. Freitas, C. Vargas-Lopes, et al. 2008. Increased brain D-amino acid oxidase (DAAO) activity in schizophrenia. Schizophr. Res. 101: 76-83.
144. Stone, T.W. 1993. Neuropharmacology of quinolinic and kynurenic acids. Pharmacol. Rev. 45: 309-379.
145. Schwarcz, R., A. Rassoulpour, H.Q. Wu, et al. 2001. Increased cortical kynurenate content in schizophrenia. Biol. Psychiatry 50: 521-530.
146. Erhardt, S., K. Blennow, C. Nordin, et al. 2001. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci. Lett. 313: 96-98.
147. Wonodi, I., O.C. Stine, K.V. Sathyasaikumar, et al. 2011. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Arch. Gen. Psychiatry 68: 665-674.
148. Sheng, M., B.L. Sabatini & T.C. Sudhof . 2012. Synapses and Alzheimer's disease. Cold Spring Harb. Perspect. Biol. 4: a005777.
149. Cohen, R.M., K. Rezai-Zadeh, T.M. Weitz, et al. 2013. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J. Neurosci. 33: 6245-6256.
150. Mcconnell, M.J., M.R. Lindberg, K.J. Brennand, et al. 2013. Mosaic copy number variation in human neurons. Science 342: 632-637.
151. Lewis, D.A. 2002. The human brain revisited: opportunities and challenges in postmortem studies of psychiatric disorders. Neuropsychopharmacology 26: 143-154.
152. Chandrakala, M.V., S.R. Marcus, H.A. Nadiger, et al. 1987. Acute and long-term effects of chlorpromazine on glutamine synthetase and glutaminase in rat brain. J. Neurochem. 49: 32-34.
153. Cook, J.F., D.F. Hill, B.M. Snively, et al. 2014. Cognitive impairment in rapid-onset dystonia-parkinsonism. Mov Disord. 29(Suppl 3): 344-350.
154. Pietersen, C.Y., M.P. Lim, L. Macey, et al. 2011. Neuronal type-specific gene expression profiling and laser-capture microdissection. Methods Mol. Biol. 755: 327-343.
155. O'Connor, J.A. & S.E. Hemby . 2007. Elevated GRIA1 mRNA expression in layer II/III and V pyramidal cells of the DLPFC in schizophrenia. Schizophr. Res. 97: 277-288.
156. Vogel, C. & E.M. Marcotte . 2012. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. 13: 227-232.
157. Macdonald, M.L., E. Ciccimaro, A. Prakash, et al. 2012. Biochemical fractionation and stable isotope dilution liquid chromatography-mass spectrometry for targeted and microdomain-specific protein quantification in human postmortem brain tissue. Mol. Cell Proteomics. 11: 1670-1681.
158. Pantelis, C., M. Yucel, S.J. Wood, et al. 2005. Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. Schizophr. Bull. 31: 672-696.
159. Maletic-Savatic, M., R. Malinow & K. Svoboda . 1999. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283: 1923-1927.
160. Xie, Z., R.L. Huganir & P. Penzes . 2005. Activity-dependent dendritic spine structural plasticity is regulated by small GTPase Rap1 and its target AF-6. Neuron 48: 605-618.
161. Xie, Z., D.P. Srivastava, H. Photowala, et al. 2007. Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron 56: 640-656.
162. Mckinney, R.A., M. Capogna, R. Durr, et al. 1999. Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nat. Neurosci. 2: 44-49.
163. Cheng, H.W., J.A. Rafols, H.G. Goshgarian, et al. 1997. Differential spine loss and regrowth of striatal neurons following multiple forms of deafferentation: a Golgi study. Exp. Neurol. 147: 287-298.
164. Sa, S.I., P.A. Pereira, M.M. Paula-Barbosa, et al. 2010. Role of neural afferents as mediators of estrogen effects on the hypothalamic ventromedial nucleus. Brain Res. 1366: 60-70.
165. Devito, L.M., D.T. Balu, B.R. Kanter, et al. 2011. Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology. Genes Brain Behav. 10: 210-222.
166. Balu, D.T., A.C. Basu, J.P. Corradi, et al. 2012. The NMDA receptor co-agonists, D-serine and glycine, regulate neuronal dendritic architecture in the somatosensory cortex. Neurobiol. Dis. 45: 671-682.
167. Liu, B.H., G.K. Wu, R. Arbuckle, et al. 2007. Defining cortical frequency tuning with recurrent excitatory circuitry. Nat. Neurosci. 10: 1594-1600.
168. Kaur, S., H.J. Rose, R. Lazar, et al. 2005. Spectral integration in primary auditory cortex: laminar processing of afferent input, in vivo and in vitro. Neuroscience 134: 1033-1045.
169. Javitt, D.C., A. Shelley & W. Ritter . 2000. Associated deficits in mismatch negativity generation and tone matching in schizophrenia. Clin. Neurophysiol. 111: 1733-1737.
170. Strous, R.D., N. Cowan, W. Ritter, et al. 1995. Auditory sensory ("echoic") memory dysfunction in schizophrenia. Am. J. Psychiatry 152: 1517-1519.
171. Javitt, D.C., P. Doneshka, S. Grochowski, et al. 1995. Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia. Arch. Gen. Psychiatry 52: 550-558.
172. Javitt, D.C., R.D. Strous, S. Grochowski, et al. 1997. Impaired precision, but normal retention, of auditory sensory ("echoic") memory information in schizophrenia. J. Abnorm. Psychol. 106: 315-324.
173. Javitt, D.C., M. Steinschneider, C.E. Schroeder, et al. 1994. Detection of stimulus deviance within primate primary auditory cortex: intracortical mechanisms of mismatch negativity (MMN) generation. Brain Res. 667: 192-200.
174. Ehrlichman, R.S., C.R. Maxwell, S. Majumdar, et al. 2008. Deviance-elicited changes in event-related potentials are attenuated by ketamine in mice. J. Cogn Neurosci. 20: 1403-1414.
175. Umbricht, D., L. Schmid, R. Koller, et al. 2000. Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch. Gen. Psychiatry 57: 1139-1147.
176. Landen, M., P. Davidsson, C.G. Gottfries, et al. 2002. Reduction of the synaptophysin level but normal levels of glycerophospholipids in the gyrus cinguli in schizophrenia. Schizophr. Res. 55: 83-88.
177. Breese, C.R., R. Freedman & S.S. Leonard . 1995. Glutamate receptor subtype expression in human postmortem brain tissue from schizophrenics and alcohol abusers. Brain Res. 674: 82-90.
178. Eastwood, S.L., R.W. Kerwin & P.J. Harrison . 1997. Immunoautoradiographic evidence for a loss of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-preferring non-N-methyl-D-aspartate glutamate receptors within the medial temporal lobe in schizophrenia. Biol. Psychiatry 41: 636-643.
179. Benes, F.M., M.S. Todtenkopf & P. Kostoulakos . 2001. GluR5, 6, 7 subunit immunoreactivity on apical pyramidal cell dendrites in hippocampus of schizophrenics and manic depressives. Hippocampus 11: 482-491.
180. Clinton, S.M., V. Haroutunian & J.H. Meador-Woodruff . 2006. Up-regulation of NMDA receptor subunit and post-synaptic density protein expression in the thalamus of elderly patients with schizophrenia. J. Neurochem. 98: 1114-1125.
181. Schizophrenia Working Group of the Psychiatric Genomics Consortium. 2014. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511: 421-427.