Why D-neuron? Importance in schizophrenia research


Recent pharmacological discovery on trace amine-associated receptor, type 1(TAAR1) has emphasized importance of trace amines in pathogenesis of psychoses, such as schizophrenia. TAAR1 has many ligands, including tyramine, β-phenylethylamine (PEA), amphetamines, and 3’-iodothyronamine. So-called D-neurons are putative producer of trace amines, endogenous ligands of TAAR1. The D-neuron is defined “the aromatic L-amino acid decarboxylase (AADC)-containing neuron, but not dopaminergic nor serotonergic”, i.e. not containing tyrosine hydroxylase nor tryptophan hydroxylase. AADC is an enzyme, also called dopa decarboxylase (DDC). The localization of D-neurons in the central nervous system has been specified into 15 groups, from the spinal cord (D1) to striatum (D15). We showed the decrease of D-neurons in D15 in postmortem brains of schizophrenia, where midbrain dopamine (DA) neurons are heavily innervated. Decrease of D-neurons may cause reduction of trace amines in the striatum, and may also decrease stimulation of TAAR1 on striatal terminals of ventral tegmental area (VTA) DA neurons. This might increase firing frequency of VTA DA neurons, and causes DA hyperactivity in the striatum and nucleus accumbens. In the present article, the author introduces the novel theory, “D-cell hypothesis”, for mesolimbic DA hyperactivity of schizophrenia. Some clinical and/or experimental evidences that support this hypothesis are mentioned. The D-neuron, as a trace amine producer, is a clue for elucidating pathogenesis of psychoses, as well as human mental functions. Thus, signal transduction of D-neurons should be investigated.

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Ikemoto, K. (2012) Why D-neuron? Importance in schizophrenia research. Open Journal of Psychiatry, 2, 393-398. doi: 10.4236/ojpsych.2012.224055.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Hokfelt, T., Ljungdahl, A., Fuxe, K. and Takashima, N. (1974) Dopamine nerve terminals in the rat limbic cortex: Aspects of the dopamine hypothesis of schizophrenia. Science, 184, 177-179. doi:10.1126/science.184.4133.177
[2] Toru, M., Nishikawa, T., Mataga, N. and Takashima, N. (1982) Dopamine metabolism increases in post-mortem schizophrenic basal ganglia. Journal of Neural Transmission, 54, 181-191. doi:10.1007/BF01254928
[3] Watis, L., Chen, S.H., Chua, H.C., Chong, S.A. and Sim, K. (2008) Glutamatergic abnormalities of the thalamus in schizophrenia: A systematic review. Journal of Neural Transmission, 115, 493-511. doi:10.1007/s00702-007-0859-5
[4] Olbrich, H.M., Valerius, G., Rüsch, N., Buchert, M., Thiel, T., Hennig, J., Ebert, D. and Van Elst, L.T. (2008) Frontolimbic glutamate alterations in first episode schizophrenia: Evidence from a magnetic resonance spectroscopy study. World Journal of Biological Psychiatry, 9, 59-63. doi:10.1080/15622970701227811
[5] Christison, G.W., Casanova, M.F., Weinberger, D.R., Rawlings, R. and Kleinman, J.E. (1989) A quantitative investigation of hippocampal pyramidal cell size, shape, and variability of orientation in schizophrenia. Archives of General Psychiatry, 46, 1027-1032. doi:10.1001/archpsyc.1989.01810110069010
[6] McGlashan, T.H. and Hoffman, R.E. (2000) Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Archives of General Psychiatry, 57, 637-648. doi:10.1001/archpsyc.57.7.637
[7] Duan, X., Chang, J.H., Ge, S., Faulkner, R.L., Kim, J.Y., Kitabatake, Y., Liu, X.B., Yang, C.H., Jordan, J.D., Ma, D.K., Liu, C.Y., Ganesan, S., Cheng, H.J., Ming, G.L., Lu, B. and Song, H. (2007) Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell, 130, 1146-1158. doi:10.1016/j.cell.2007.07.010
[8] Reif, A., Fritzen, S., Finger, M., Strobel,A., Lauer, M., Schmitt, A. and Lesch, K.P. (2006) Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Molecular Psychiatry, 11, 514-522. doi:10.1038/sj.mp.4001791
[9] Ikemoto, K., Nishimura, A., Oda, T.,Nagatsu, I. and Nishi, K. (2003) Number of striatal D-neurons is reduced in autopsy brains of schizophrenics. Legal Medicine, 5, S221-S224. doi:10.1016/S1344-6223(02)00117-7
[10] Jaeger, C.B.,Teitelman, G., Joh, T.H., Albert, V.R., Park, D.H. and Reis, D.J. (1983) Someneurons of the rat central nervous system contain aromatic-L-aminoacid decarboxylase but not monoamines. Science, 219, 1233-1235. doi:10.1126/science.6131537
[11] Boulton, A.A. (1971) Amines and theories in psychiatry. The Lancet, 2, 7871.
[12] Boulton, A.A. and Juorio, A.V. (1979) Thetyramines: Are they involved in thepsychoses? Biological Psychiatry, 14, 413-419.
[13] Komori, K., Fujii, T., Karasawa, N.,Yamada, K., Sakai, M. and Nagatsu, I. (1991) Some neurons of the mouse cortex and caudo-putamen contain aromatic L-amino acid decarboxylase but monoamines. Acta Histochemicaet Cytochemica, 24, 571-577. doi:10.1267/ahc.24.571
[14] Jaeger, C.B., Ruggiero, D.A., Albert, V.R., Joh, T.H. and Reis, D.J. (1984) Immunocytochemical localization of aromatic-L-amino acid decarboxylase. In: Bjorklund, A. and Hokfelt, T., Eds., Handbook of Chemical Neuroanatomy 2: Classical Transmitters in the CNS, Part I, Elsevier, Amsterdam, 387-408.
[15] Jaeger, C.B., Ruggiero, D.A., Albert, V.R.,Park, D.H., Joh, T.H. and Reis, D.J. (1984) Aromatic L-amino acid decarboxylase in the rat brain: Immunocytochemical localization in neurons of the rat brain stem. Neuroscience, 11, 691-713. doi:10.1016/0306-4522(84)90053-8
[16] Tashiro, Y., Kaneko, T., Sugimoto, T., Nagatsu, I., Kikuchi, H. and Mizuno, N. (1989) Striatal neurons with aromatic L-amino acid decarboxylase-like immunore-activity in the rat. Neuroscience Letters, 100, 29-34. doi:10.1016/0304-3940(89)90655-1
[17] Mura, A., Linder, J.C., Young, S.J. and Groves, P.M. (2000) Striatal cells containing aromatic L-amino acid decarboxylase: An immunohistochemical comparison with other classes of striatal neurons. Neuroscience, 98, 501-511. doi:10.1016/S0306-4522(00)00154-8
[18] Ikemoto, K., Kitahama, K., Jouvet, A., Arai, R., Nishi- mura, A., Nishi, K. and Nagatsu, I. (1997) Demonstration of L-dopa decarboxylating neurons specific to human striatum. Neuroscience Letters, 232, 111-114. doi:10.1016/S0304-3940(97)00587-9
[19] Ikemoto, K., Kitahama, K., Jouvet, A., Nishimura, A., Nishi, K., Maeda, T. and Arai, R. (1998) A dopamine-synthesizing cell group demonstrated in the human basal forebrain by dual labeling immunohistochemical technique of tyrosine hydroxylase and aromatic L-amino acid decarboxylase. Neuroscience Letters, 243, 129-132. doi:10.1016/S0304-3940(98)00103-7
[20] Kitahama, K., Ikemoto, K., Jouvet, A., Nagatsu, I., Sakamoto, N. and Pearson, J. (1998) Aromatic L-amino acid decarboxylase and tyrosine hydroxylase immuno-histochemistry in the adult human hypothalamus. Journal of Chemical Neuroanatomy, 16, 43-55. doi:10.1016/S0891-0618(98)00060-X
[21] Kitahama, K., Ikemoto, K., Jouvet, A.,Araneda, S., Nagatsu, I., Raynaud, B., Nishimura, A., Nishi, K. and Niwa, S. (2009) Aromatic L-amino acid decarboxylase-immunoreactive structures in human midbrain, pons, and medulla. Journal of Chemical Neuroanatomy, 38, 130-140. doi:10.1016/j.jchemneu.2009.06.010
[22] Ikemoto, K. (2004) Significance of human striatal D-neurons: Implications in neuropsychiatric functions. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 28, 429-434. doi:10.1016/j.pnpbp.2003.11.017
[23] Bunzow, J.R., Sonders, M.S., Arttamangkul, S., Harrison, L.M., Zhang, G., Quigley, D.I., Darland, T., Suchland, K.L., Pasumamula, S., Kennedy, J.L., Olson, S.B., Magenis, R.E., Amara, S.G. and Grandy, D.K. (2001) Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Molecular Pharmacology, 60, 1181-1188.
[24] Borowsky, B., Adham, N., Jones, K.A., Raddatz, R., Artymyshyn, R., Ogozalek, K.L., Durkin, M.M., Lakhlani, P.P., Bonini, J.A., Pathirana, S., Boyle, N., Pu, X., Kouranova, E., Lichtblau, H., Ochoa, F.Y., Branchek, T.A. and Gerald, C. (2001) Trace amines: Identification of a family of mammalian G protein-coupled receptors. Proceedings of the National Academy of Sciences of the United States of America, 98, 8966-8971.
[25] Miller, G.M. (2011) The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity. Journal of Neurochemistry, 116, 164-176. doi:10.1111/j.1471-4159.2010.07109.x
[26] Xie, Z. and Miller, G.M. (2007) Trace amine-associated receptor 1 is a modulator of the dopamine transporter. Journal of Pharmacology and Experimental Therapeutics, 321, 128-136. doi:10.1124/jpet.106.117382
[27] Xie, Z. and Miller, G.M. (2009) Trace amine-associated receptor 1 as a monoaminergic modulator in brain. Biochemical Pharmacology, 78, 1095-1104. doi:10.1016/j.bcp.2009.05.031
[28] Lindemann, L., Meyer, C.A., Jeanneau, K., Bradaia, A., Ozmen, L., Bluethmann, H., Bettler, B., Wettstein, J.G., Borroni, E., Moreau, J.L. and Hoener, M.C. (2008) Trace amine-associated receptor 1 modulates dopaminergic activity. Journal of Pharmacology and Experimental Therapeutics, 324, 948-956. doi:10.1124/jpet.107.132647
[29] Zucchi, R., Chiellini, G., Scanlan, T.S. and Grandy, D.K. (2006) Trace amine-associated receptors and their ligands. British Journal of Pharmacology, 149, 967-978. doi:10.1038/sj.bjp.0706948
[30] Bradaia, A., Trube, G., Stalder, H., Norcross, R.D., Ozmen, L., Wettstein, J.G., Pinard, A., Buchy, D., Gassmann, M., Hoener, M.C. andBettler, B. (2009) The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proceedings of the National Academy of Sciences of the United States of America, 106, 20081-20086.
[31] Revel, F.G., Moreau, J.L., Gainetdinov, R.R., Bradaia, A., Sotnikova, T.D., Mory, R., Durkin, S., Zbinden, K.G., Norcross, R., Meyer, C.A., Metzler, V., Chaboz, S., Ozmen, L., Trube, G., Pouzet, B., Bettler, B., Caron, M.G., Wettstein, J.G and Hoener, M.C. (2011) TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proceedings of the National Academy of Sciences of the United States of America, 108, 8485-8490.
[32] Panas, H.N., Lynch, L.J., Vallender, E.J., Xie, Z., Chen, G.L., Lynn, S.K., Scanlan, T.S. and Miller, G.M. (2010) Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice. Journal of Neuroscience Research, 88, 1962-1969.
[33] Wolinsky, T.D., Swanson, C.J., Smith, K.E., Zhong, H., Borowsky, B., Seeman, P., Branchek, T. and Gerald, C.P. (2007) The trace amine 1 receptor knockout mouse: An animal model with relevance to schizophrenia. Genes, Brain and Behavior, 6, 628-639. doi:10.1111/j.1601-183X.2006.00292.x
[34] Ikemoto, K. (2012) Are D-neurons and trace amine associated receptor, type 1 involved in mesolimbic dopamine hyperactivity of schizophrenia? Medicinal Chemistry, 2. doi:10.4172/2161-0444.1000111
[35] Ikemoto, K. (2012) NSC-induced D-neurons are decreased in striatum of schizophrenia: Possible cause of mesolimbic dopamine hyperactivity. Stem Cell Discovery, 2, 58-61. doi:10.4236/scd.2012.22009
[36] Ikemoto, K. (2012) “D-cell hypothesis” of schizophrenia: Possible theory for mesolimbic dopamine hyperactivity. World Journal of Neuroscience, 2, 141-144. doi:10.4236/wjns.2012.23021
[37] Ikemoto, K. (2012) D-cell hypothesis: Pathogenesis of mesolimbic dopamine hyperactivity of schizophrenia. Journal of Behavior and Brain Science, 2, 411-414. doi:10.4236/jbbs.2012.23048
[38] Ikemoto, K. (2008) Striatal D-neurons: In new viewpoints for neuropsychiatric research using post-mortem brains. Fukushima Journal of Medical Science, 54, 1-3.
[39] Degreef, G., Ashtari, M., Bogerts, B., Bilder, R.M., Jody, D.N., Alvir, J.M. and Lieberman, J.A. (1992) Volumes of ventricular system subdivisions measured from magnetic resonance images in first-episode schizophrenic patients. Archives of General Psychiatry, 49, 531-537. doi:10.1001/archpsyc.1992.01820070025004
[40] Horga, G., Bernacer, J., Dusi, N., Entis, J., Chu, K., Hazlett, E.A., Haznedar, M.M., Kemether, E., Byne, W. and Buchsbaum, M.S. (2011) Correlations between ventricular enlargement and gray and white matter volumes of cortex, thalamus, striatum, and internal capsule in schizophrenia. European Archives of Psychiatry and Clinical Neuroscience, 261, 467-476. doi:10.1007/s00406-011-0202-x
[41] Kippin, T.E., Kapur, S. and van der Kooy, D. (2005) Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. The Journal of Neuroscience, 25, 5815-5023. doi:10.1523/JNEUROSCI.1120-05.2005
[42] Lee, A.H., Lange, C., Ricken, R., Hellweg, R. and Lang, U.E. (2011) Reduced brain-derived neurotrophic factor serum concentrations in acute schizophrenic patients increase during antipsychotic treatment. Journal of Clinical Psychopharmacology, 31,334-346. doi:10.1097/JCP.0b013e31821895c1
[43] Bortolato, M., Godar, S.C., Davarian, S., Chen, K. and Shih, J.C. (2009) Behavioral disinhibition and reduced anxiety-like behaviors in monoamine oxidase B-deficient mice. Neuropsychopharmacology, 34, 2746-2757. doi:10.1038/npp.2009.118
[44] Niwa, S.-I., Kunii, Y., Wada, A., Yang, Q.-H. and Ikemoto, K. (2009) Post-mortem brain studies in schizophrenia. Japanese Journal of Clinical Psychopharmacology, 12, 148-168.
[45] Sabelli, H.C. and Mosnaim, A.D. (1974) Phenylethylamine hypothesis of affective behavior. American Journal of Psychiatry, 131, 695-699.

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