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D-Neuron: Is it Ligand-Producing Neuron of Taar1? From Schizophrenia Research

Keiko Ikemoto

Recent pharmacological studies has been shown the importance of trace amine-associated receptor, type 1 (TAAR1), a subtype of trace amine receptors, as a prospective target receptor for novel neuroleptics. In the present article, the author shows D-neuron research in psychiatric field. Although dopamine (DA) dysfunction is a well-known hypothesis of etiology of schizophrenia, its molecular basis has not yet been clarified. To explain this, modulating function of trace amines on DA neurotransmission was considered. The TAAR1 has a large number of ligands, including tyramine, β-phenylethylamine and methamphetamine that influence on human mental state. 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. Previously, the author and her colleagues reported D-neuron decrease in the striatum including nucleus accumbens of postmortem brains of patients with schizophrenia. This implies the decrease of trace amine synthesis and consequent reduction of TAAR1 stimulation on terminals of midbrain VTA DA neurons, and may lead to mesolimbic DA hyperactivity in schizophrenia. Striatal D-neuron decrease of postmortem brains, due to neural stem cell dysfunction in the subventricular zone of lateral ventricle, might be pivotal in etiology of schizophrenia. The new “D-cell hypothesis”, in which D-neurons and TAAR1 are involved, is concordant with recent reports showing effectiveness of TAAR1 ligands for schizophrenia model animals.