Advances in Biosensors and Bioelectronics (ABB) Volume 2 Issue 3, September 2013

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D-neuron in Schizophrenia Research

Keiko Ikemoto
Department of Psychiatry, Iwaki Kyoritsu General Hospital,
Iwaki, 973-8555, Japan
ikemoto@iwaki-kyoritsi.iwaki.fukushima.jp
Abstract
Although dopamine (DA) dysfunction is a well-known
hypothesis for etiology of schizophrenia, molecular basis of
mesolimbic DA hyperactivity has not yet been clarified. To
explain this, modulating function of trace amines on DA
neurotransmission and the decreased number of striatal Dneurons, trace amine-producing neurons, were considered.
Notably, Trace Amine-Associated Receptor, Type 1 (TAAR1),
a subtype of trace amine receptors, with a large number of
ligands, including tyramine, -phenylethylamine and
methamphetamine that have influence on human mental
state, is now regarded as a targeted receptor for novel
neuroleptics. Reduced stimulation of TAAR1 on DA neurons
in the midbrain ventral tegmental area (VTA) has been
revealed to increase firing frequency of VTA DA neurons.
The decrease of D-neurons in the striatum and nucleus
accumbens of postmortem brains of patients with
schizophrenia has been reported. This implies the decrease
of trace amine synthesis and consequent reduction of the
stimulation of TAAR1 on terminals of midbrain VTA DA
neurons, and may lead to mesolimbic DA hyperactivity in
schizophrenia. The decrease of striatal D-neurons of
postmortem brains of schizophrenia might be due to neural
stem cell dysfunction in the subventricular zone of lateral
ventricle. The new D-cell hypothesis, in which D-neurons
and TAAR1 are involved, is in agreement with recent reports
of TAAR1 research using animal models.
Keywords
Dopamine; D-neuron; Trace Amine; Schizophrenia; TAAR1

Introduction
Dopamine (DA) dysfunction (Hokfelt et al. 1974, Toru
et al. 1982) glutamate dysfunction (Watis et al. 2008,
Olbrich et al. 2008) neurodevelopmental deficits
(Christison et al. 1989, McGlashan et al. 2000) or neural
stem cell dysfunction (Reif et al. 2006, Duan et al. 2007)
are well-known hypotheses for etiology of schizophrenia.
DA dysfunction hypothesis suggested that mesolimbic
DA hyperactivity caused positive symptoms such as
paranoid-hallucinatory state of schizophrenia (Hokfelt
et al. 1974, Toru et al. 1982). It is also explained by the
efficacy of DA D2 blockers for paranoid-hallucinatory
state and also by hallucino-genic acts of DA stimulants
including methamphet-amine or amphetamine (Hokfelt

et al. 1974, Toru et al. 1982). Glutamate dysfunction

theory was induced by the fact that intake of
phencyclidine (PCP), an antagonist of NMDA receptor,
produces equivalent to negative symptoms of
schizophrenia, such as withdrawal or flattened affect,
as well as positive symptoms (Watis et al. 2008,
Olbrich et al. 2008). The neurodevelopmental deficits
hypothesis implicates that schizophrenia is the
consequence of prenatal abnormalities resulting from
the interaction of genetic and environmental factors
(Christison et al. 1989, McGlashan et al. 2000). Neural
stem cell dysfunction has also been shown to be a
cause of schizophrenia (Reif et al. 2006, Duan et al.
2007). Although mesolimbic DA hyperactivity
(Hokfelt et al. 1974, Toru et al. 1982) has been well
documented in pathogenesis of schizophrenia, the
molecular basis of this mechanism has not yet been
detailed. In the present article, the author hypothesized
the involvement of striatal D-neurons and trace amineassociated receptor, type 1 (TAAR1) in the pathogenesis
of mesolimbic DA hyperactivity of schizophrenia
(Ikemoto et al. 2003).
D-neuron
The D-cell described by Jaeger et al. in 1983 in the
rat central nervous system and defined as the nonmonoaminergic aromatic L-amino acid decarboxylase
(AADC)-containing cell contains AADC but neither
dopamine nor serotonin (Jaeger et al. 1983). It can also
produce trace amines (Boulton 1974, Boulton & Juorio
1979), and may act as an APUD (amine precursor
uptake and decarboxylation) system that takes up
amine precursors and transforms them to amines by
decarboxylation (Komori et al. 1991). The localizations
of D-cells are specified into 14 groups, from D1 (the
spinal cord) to D14 (the bed nucleus of stria terminalis)
in caudo-rostral orders of the rat central nervous
system using AADC immunohistochemistry (Jaeger et
al. 1984a, b). In this usage, the classification term D
means decarboxylation. In rodents (Tashiro et al. 1989,
Komori et al. 1991, Mura et al. 2000), a small number
of D-cells in the striatum have been rostrally described
and confirmed to be neurons by electron-microscopic
35

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Advances in Biosensors and Bioelectronics (ABB) Volume 2 Issue 3, September 2013

observation (Komori et al. 1991). The author with coworkers reported in 1997, dopa-decarboxylating
neurons specific to the human striatum (Ikemoto et
al.1997, 1998, Kitahama et al. 1998, 2009), that is, Dneurons in the human striatum (Kitahama et al. 1998,
Ikemoto 2004) (classified to be D15) (Kitahama et al.
1998), and later, the reduction of the number of Dneurons in the striatum, including nucleus accumbens
of patients with schizophrenia (Ikemoto et al. 2003,
Ikemoto 2004).

to the decrease of the amounts of trace amines in the

nuclei, though direct evidences have not yet been
demonstrated. Enlargement of the lateral ventricle
(Degreef et al. 1992, Horga et al 2011), a usual finding
documented in brain imaging studies of schizophrenia,
is possibly due to dysfunction of neural stem cells of
the subventricular zone (Reif et al. 2006, Duan et al.
2007).

Trace Amine-Associated Receptor, Type 1

(TAAR1)
Cloning of trace amine receptors in 2001 (Borowsky et al
2001, Bunzow et al. 2001), elicited enormous efforts to
explore signal transduction of these G-protein coupled
receptors whose genes are located on chromosome
focus 6q23.1 (Miller 2011). The receptors have been
shown to co-localize with dopamine or adrenaline
transporters in monoamine neurons and to modulate
the functions of monoamines (Xie & Miller 2007, 2009,
Lindemann et al. 2008). The trace amine-associated
receptor, type 1 (TAAR1) having a large number of
ligands, including tyramine, -phenylethylamine
(PEA) and psychostimulants, for example methamphetamine, 3, 4-methylenedioxymethamphetamine
(MDMA) and lysergic acid diethylamide (LSD)
(Bunzow et al. 2001, Zucchi et al. 2006, Miller 2011),
has become a targeted receptor to explore novel
neuroleptics (Bradaia et al. 2009, Revel et al. 2013).
TAAR1 knockout mice showed schizophrenia-like
behaviors with a deficit in prepulse inhibition, as well
as greater locomotor response to amphetamine and
released more DA (and noradrenaline) in response to
amphetamine than wild type mice (Panas et al. 2010).
It has been shown that TAAR1 has a thermoregulatory
function (Wolinsky et al. 2007). It was clarified that
increased stimulation of TAAR1 receptors on cell
membranes of DA neurons in the midbrain ventral
tegmental area (VTA) reduced firing frequency of
VTA DA neurons (Bradaia et al. 2009, Panas et al. 2010,
Revel et al. 2013).
A New D-Cell Hypothesis of Schizophrenia
A new theory, D-cell hypothesis, to explain
mesolimbic DA hyperactivity in pathogenesis of
schizophrenia is shown in Figure. In brains of patients
with schizophrenia, dysfunction of neural stem cells in
the subventricular zone of lateral ventricle causes the
decrease of D-neurons in the striatum and nucleus
accumbens (Reif et al. 2006, Ikemoto 2008). This leads

36

The reduction of TAAR1 stimulation on DA terminals

of VTA DA neurons, caused by trace amine decrease,
would increase the firing frequency of VTA DA
neurons (Bradaia et al. 2009, Panas et al. 2010), leading
to the increase of DA release in the nucleus accumbens,
and then resulting in mesolimbic DA hyperactivity. It
has been shown that D2 stimulation of neural stem
cells in the striatum inhibited forebrain neural stem
cell proliferation (Kippin et al. 2005). Then, striatal DA
hyperactivity may accelerate D-neuron decrease,
which accelerates hyperactivity of meso-limbic DA
system. Actions of D2 blocking agents in
pharmacotherapy of schizophrenia might partially be
explained by the decrease of inhibition to forebrain
neural stem cell proliferations. It is consistent with
clinical evidences that initial pharmacotherapy using
D2 blockers is proved to be critical to prevent
progressive pathognomonic procedures of schizophrenia.
Conclusions
The D-neuron, i.e., the trace amine-producing neuron,
is a clue for pathogenesis schizophrenia. Further
exploration of signal transduction of the D-neuron is
essential.
ACKNOWLEDGMENT

The present study was supported by Grant-in-Aid for

Scientific Research from Japan Society for the
Promotion of Science (C-22591265).

Advances in Biosensors and Bioelectronics (ABB) Volume 2 Issue 3, September 2013

REFERENCES

Ikemoto K, Kitahama K, Jouvet A, Arai R, Nishimura A, et al.

Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn

R, et al. (2001) Trace amines: identification of a family of
mammalian G protein-coupled receptors. Proc Natl Acad
Sci USA 98: 8966-8971.
Boulton AA (1974) Amines and theories in psychiatry.The
Lancet 304: 52-53.
Boulton AA, Juorio AV (1979) The tyramines: are they
involved in the psychoses? Biol Psychiatry 14: 413-419.
Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, et al.
(2009) The selective antagonist EPPTB reveals TAAR1mediated

www.seipub.org/abb

regulatory

mechanisms

in

dopaminergic

neurons of the mesolimbic system. Proc Natl Acad Sci

USA 106: 20081-20086.
Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM,
Zhang G, et al. (2001) Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and
metabolites of the catecholamine neurotransmitters are
agonists of a rat trace amine receptor. Mol Pharmacol 60:
1181-1188.

(1997) Demonstration of L-dopa decarboxylating neurons

specific to human striatum. Neurosci Lett 232: 111-114.
Ikemoto K, Nagatsu I, Kitahama K, Jouvet A, Nishimura A,
et al. (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.
Neurosci Lett 243: 129-132.
Ikemoto K, Nishimura A, Oda T, Nagatsu I, Nishi K (2003)
Number of striatal D-neurons is reduced in autopsy
brains of schizophrenics. Leg Med (Tokyo) Suppl 1: S221S224.
Ikemoto K (2004) Significance of human striatal D-neurons:
implications

in

neuropsychiatric

functions.

Prog

Neuropsychopharmacol Biol Psychiatry 28: 429-434.

Ikemoto K (2008) Striatal D-neurons: in new viewpoints for
neuropsychiatric research using post-mortem brains.
Fukushima J Med Sci 54: 1-3.
Jaeger CB, Teitelman G, Joh TH, Albert VR, Park DH, et al.

Christison GW, Casanova MF, Weinberger DR, Rawlings R,

(1983) Some neurons of the rat central nervous system

Kleinman JE (1989) A quantitative investigation of

contain aromatic-L-amino-acid decarboxylase but not

hippocampal pyramidal cell size, shape, and variability

monoamines. Science 219: 1233-1235.

of orientation in schizophrenia. Arch Gen Psychiatry 46:

1027-1032.
Degreef G, Ashtari M, Bogerts B, Bilder RM, Jody DN, et al.
(1992) Volumes of ventricular system subdivisions

Jaeger CB, Ruggiero DA, Albert VR, Park DH, Joh TH, et al.
(1984a) Aromatic L-amino acid decarboxylase in the rat
brain: Immunocytochemical localization in neurons of
the rat brain stem. Neuroscience 11: 691-713.

measured from magnetic resonance images in first-

Jaeger CB, Ruggiero DA, Albert V R, Joh TH, Reis DJ

episode schizophrenic patients. Arch Gen Psychiatry 49:

(1984b) Immunocytochemical localization of aromatic-

531-537.

L-amino acid decarboxylase, in Handbook of Chemical

Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, et al. (2007)

Disrupted-In-Schizophrenia 1 regulates integration of
newly generated neurons in the adult brain. Cell 130:
1146-1158.
Hokfelt T, Ljungdahl A, Fuxe K, Johansson O (1974)
Dopamine nerve terminals in the rat limbic cortex:
aspects of the dopamine hypothesis of schizophrenia.
Science 184: 177-179.
Horga G, Bernacer J, Dusi N, Entis J, Chu K, et al. (2011)
Correlations between ventricular enlargement and gray
and white matter volumes of cortex, thalamus, striatum,

Neuroanatomy. Classical Transmitters in the CNS, Part I.

(Vol 2), Elsevier, Amsterdam 387-408.
Kippin TE, Kapur S, van der Kooy D (2005) Dopamine
specifically

inhibits

forebrain

neural

stem

cell

proliferation, suggesting a novel effect of antipsychotic

drugs. J Neurosci 25: 5815-5823.
Kitahama K, Ikemoto K, Jouvet A, Nagatsu I, Sakamoto N, et
al. (1998) Aromatic L-amino acid decarboxylase and
tyrosine hydroxylase immunohistochemistry in the adult
human hypothalamus. J Chem Neuroanat 16: 43-55.
Kitahama K, Ikemoto K, Jouvet A, Araneda S, Nagatsu I, et

and internal capsule in schizophrenia. Eur Arch

al.

Psychiatry Clin Neurosci 261: 467-476.

immunoreactive structures in human midbrain, pons,

(2009)

Aromatic

L-amino

acid

decarboxylase-

37

www.seipub.org/abb

Advances in Biosensors and Bioelectronics (ABB) Volume 2 Issue 3, September 2013

Neural stem cell proliferation is decreased in schizophrenia,

and medulla. J Chem Neuroanat 38: 130-140.

Komori K, Fujii T, Karasawa N, Yamada K, Nagatsu I, et al.

but not in depression. Mol Psychiatry 11: 514-522.

(1991) Some neurons of the mouse cortex and caudo-

Revel FG, Moreau JL, Hoener MC, et al: (2013) A new

putamen contain aromatic L-amino acid decarboxylase

perspective for schizophrenia: TAAR1 agonists reveal

but not monoamines. Acta Histochem Cytochem 24: 571-

antipsychotic- and antidepressant-like activity, improve

577.

cognition and control body weight. Mol Psychiatry 18:

Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L,

543-556.

et al. (2008) Trace amine-associated receptor 1 modulates

Tashiro Y, Kaneko T, Sugimoto T, Nagatsu I, Kikuchi H, et al.

dopaminergic activity. J Pharmacol Exp Ther 324: 948-

(1989) Striatal neurons with aromatic L-amino acid

956.

decarboxylase-like immunoreactivity in the rat. Neurosci

McGlashan TH, Hoffman RE (2000) Schizophrenia as a

disorder

of

developmentally

reduced

synaptic

Lett 100: 29-34.

Toru M, Nishikawa T, Mataga N, Takashima N (1982)
Dopamine

connectivity. Arch Gen Psychiatry 57: 637- 648.

metabolism

increases

in

post-mortem

Miller GM (2011) The emerging role of trace amine-

schizophrenic basal ganglia. J Neural Transm 54: 181-191.

associated receptor 1 in the functional regulation of

Watis L, Chen SH, Chua HC, Chong SA, Sim K (2008)

monoamine transporters and dopaminergic activity. J

Glutamatergic

Neurochem 116: 164-176.

schizophrenia: a systematic review. J Neural Transm 115:

Mura A, Linder JC, Young SJ, Groves PM (2000) Striatal cells

of

the

thalamus

in

493-511.

containing aromatic L-amino acid decarboxylase: an

Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B,

immunohistochemical comparison with other classes of

et al. (2007) The Trace Amine 1 receptor knockout mouse:

striatal neurons. Neuroscience 98: 501-511.

an animal model with relevance to schizophrenia. Genes

Olbrich HM, Valerius G, Rsch N, Buchert M, Thiel T, et al.

Brain Behav 6: 628-639.

(2008) Frontolimbic glutamate alterations in first episode

Xie Z, Miller GM (2007) Trace amine-associated receptor 1 is

schizophrenia: evidence from a magnetic resonance

a modulator of the dopamine transporter. J Pharmacol

spectroscopy study. World J Biol Psychiatry 9: 59-63.

Exp Ther 321: 128-136.

Panas HN, Lynch LJ, Vallender EJ, Xie Z, Chen GL, et al.
(2010)

Normal

thermoregulatory

responses

to

3-

iodothyronamine, trace amines and amphetamine-like

psychostimulants in trace amine associated receptor 1
knockout mice. J Neurosci Res 88: 1962-1969.
Reif A, Fritzen S, Finger M, Strobel A, Lauer M, et al. (2006)

38

abnormalities

Xie Z, Miller GM (2009) Trace amine-associated receptor 1 as a

monoaminergic modulator in brain. Biochem Pharmacol 78:
1095-1104.
Zucchi R, Chiellini G, Scanlan TS, Grandy DK (2006) Trace
amine-associated receptors and their ligands. Br J
Pharmacol 149: 967-978.