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Importance of D-neuron research in neuropsychiatry

Keiko Ikemoto

Department of Psychiatry, Iwaki Kyoritsu General Hospital, Japan

DOI: 10.15761/IMM.1000295

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Definition of “D-Neuron”

The D-neuron in the rat central nervous system (CNS) was described by Jaeger et al. [1]. Initially, they defined as “the non-monoaminergic aromatic L-amino acid decarboxylase (AADC)-containing cell”, and called the “D-cell”. AADC is an equivalent enzyme to dopa decarboxylase (DDC). The D-cell contains AADC but neither dopaminergic nor serotonergic. Then, it is natural that the D-cell is thought to produce the trace amine (TA), such as β-phenylethylamine (PEA), tyramine and tryptamine. AADC is the rate-limiting enzyme for TA synthesis. However, it is confusing that these TAs are also “monoamines”, as each TA has one amino residue.

D-cells which Jaeger et al. reported were proved to be neurons by electro-microscopic observation, and they are also called D-neurons. The latter is much more accurate nomenclature [2].

Since 2001, when the trace amine receptor was cloned, D-neurons have come to be recognized as ligand-producing neurons of the trace amine-associated receptor (TAAR).

Anatomy and species differences

The localizations of D-neurons were specified into 14 groups, from D1 (the spinal cord) to D14 (the bed nucleus of stria terminalis) in caudo-rostral orders of the rat CNS using AADC immunohistochemistry. In this usage, the classification term “D” means decarboxylation. In rodents, a small number of D-neurons in the striatum have been rostrally described. The author reported in 1997, “dopa-decarboxylating neurons specific to the human striatum”, that is, “D-neurons” in the human striatum (classified to be D15) and the nucleus accumbens (Acc, D16) (Figure 1), though monkey striatum did not contain D-neurons in these areas [3]. By using human post-mortem brain materials, D-neurons have been also described in the basal forebrain (D17) and the cerebral cortex (D18). In humans, D-neuron system is far developed in the forebrain (Figure 2).

Figure 1. Localization of D-neuron in mammalian

Figure 2. Photomicrographs of D-neurons in the human nucleus accumbens (D16).

Corresponding to anatomical nomenclature of amine neurons, that is, A group for catecholamine neurons (A1 - A16), B group for serotonergic neurons (B1 - B14), and C group for epinephrine (adrenergic) neurons (C1-C3), D group is used as the classification term for TA neurons (D1-D18) [4].

Lack of D-neurons in striatum (D15) and nucleus accumbens (D16) of post-mortem brains with schizophrenia, and D-cell (D-neuron) hypothesis

In 2003, by using pathological and legal autopsy brains of patients with schizophrenia, reduction of D-neurons in the striatum (D15) and Acc (D16) of patients with schizophrenia was also shown. This finding lead to establish D-cell hypothesis of schizophrenia, that links dopamine hypothesis to neural stem cell (NSC) dysfunction hypothesis, explaining molecular mechanisms of mesolimbic dopamine hyperactivity [2, 4].

Medicinal chemistry related to D-neuron

The human D-neuron is the ligand neuron of trace amine-associated receptor 1 (TAAR1). TAAR1 is now assumed to be a prospective target receptor of neuroleptics, including antipsychotics, antidepressants and hypnotics. Animal studies have shown the effectiveness of TAAR1 agonists and partial agonists for schizophrenia symptoms and addiction [4]. Nevertheless, D-neuron signal is yet unclear. Further studies should be conducted to elucidate detailed signals between NSC, D-neuron, trace amines, TAAR1 and dopamine.


  1. Jaeger CB, Teitelman G, Joh TH, Albert VR, Park DH, et al. (1983) Some neurons of the rat central nervous system contain aromatic-L-amino-acid decarboxylase but not monoamines. Science 219: 1233-1235. [Crossref]
  2. Ikemoto K (2015) Dopamine hypothesis is linked with neural stem cell (NSC) dysfunction hypothesis by D-Cell hypothesis (trace amine hypothesis) in etiology of schizophrenia. Biochem Physiol 4: 152.
  3. Ikemoto K, Kitahama K, Jouvet A, Arai R, Nishimura A, et al. (1997) Demonstration of L-dopa decarboxylating neurons specific to human striatum. Neurosci Lett 232: 111-114.
  4. Ikemoto K (2016) Involvement of so-called D-neuron (trace amine neuron) in the pathogenesis of schizophrenia: D-cell hypothesis, In: Trace Amine and Neurological Disorders: Potential Mechanisms and Risk Factors. Tahira Farooqui & Akhlaq A. Farooqui, Eds, Academic Press 2016: 295-307

Editorial Information


Ivan Gout
University College London
Ricardo H. Alvarez
Cancer Treatment Centers of America

Article Type

Short Communication

Publication history

Received: June 29, 2017
Accepted: July 24, 2017
Published: July 27, 2017


©2017 Ikemoto K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Ikemoto K (2017) Importance of D-neuron research in neuropsychiatry. Integr Mol Med 4: DOI: 10.15761/IMM.1000295

Corresponding author

Keiko Ikemoto

Department of Psychiatry, Iwaki Kyoritsu General Hospital, Iwaki 973-8555, Japan

Figure 1. Localization of D-neuron in mammalian

Figure 2. Photomicrographs of D-neurons in the human nucleus accumbens (D16).