D-Cell Hypothesis (Trace Amine Hypothesis) of Schizophrenia, and importance of Trace Amine-Associated Receptor, Type 1 (TAAR1)

Abstract

Mesolimbic dopamine (DA) hyperactivity is a well-known pathophysiological hypothesis of schizophrenia. The author shows a hypothesis to clarify the molecular basis of mesolimbic DA hyperactivity of schizophrenia. An immunohistochemical method was used to show D-neuron (trace amine (TA) neuron) decrease in the nucleus accumbens (Acc) of postmortem brains with schizophrenia. The striatal D-neuron decrease in schizophrenia and consequent (TAAR1) stimulation decrease onto terminals of midbrain ventral tegmental area (VTA) DA neurons induces mesolimbic DA hyperactivity of schizophrenia. Dysfunction of subventricular neural stem cells (NSC), located partially overlapping Acc is the cause of D-neuron decrease in Acc. DA hyperactivity, which inhibits NSC proliferation, causes disease progression of schizophrenia. The highlight is the rational that the “D-cell hypothesis (TA hypothesis) of schizophrenia” is a pivotal theory to link NSC dysfunction hypothesis to DA hypothesis. From a therapeutic direction, (1) TAAR1 agonists, (2) DA D2 antagonists, and (3) neurotrophic substances have potential to normalize mesolimbic DA hyperactivity. To develop novel therapeutic strategies, metabolisms of TAAR1 ligands, and NSC- and D-neuron-pathophysiology of neuropsychiatric illnesses should further be explored.