Definition of “D-Neuron”
The D-neuron in the rat central nervous system (CNS) was described by Jaeger et al. . 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 .
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 . 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) .
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 . 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.
- 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]
- 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.
- 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.
- 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