Chapter 20 - Involvement of So-Called D-Neuron (Trace Amine Neuron) in the Pathogenesis of Schizophrenia: D-Cell Hypothesis

Abstract

Schizophrenia is a mental illness, which manifests delusion, hallucination, disorganized thought, flattened affect, and impaired cognitive processes. Mesolimbic dopamine (DA) hyperactivity is a well-known pathophysiological hypothesis of schizophrenia. In this chapter, the author shows a new hypothesis to clarify the molecular basis of mesolimbic DA hyperactivity of schizophrenia. The Patent Cooperation Treaty (PCT)-required histochemical methods were used to show D-neuron (trace amine (TA) neuron) decrease in the nucleus accumbens (Acc) of postmortem brains with schizophrenia. Striatal D-neuron decrease in schizophrenia and consequent TAAR1 (TA-associated receptor, type 1) stimulation decrease onto terminals of midbrain ventral tegmental area (VTA) DA neurons induces mesolimbic DA hyperactivity of schizophrenia. Dysfunction of subventricular neural stem cells (NSCs), located partially overlapping Acc, is the cause of a D-neuron decrease in Acc. DA hyperactivity, which inhibits NSC proliferation, causes disease progression of schizophrenia. The rationale is that the “D-cell hypothesis (TA hypothesis) of schizophrenia” is a pivotal theory to link the NSC dysfunction hypothesis to the DA hypothesis. From a therapeutic direction (1) TAAR1 agonists and partial agonists, (2) DA D2 antagonists, and (3) neurotrophic substances have potential to normalize mesolimbic DA hyperactivity. To further develop strategies of novel pharmacotherapy, elucidation of NSC and D-neuron pathophysiology of neuropsychiatric illnesses is essential and remains to be explored.