¹Graduate School of Medicine, The University of Tokyo, Neuropsychiatry, Tokyo, Japan, ²The Institute of Medical Science, The University of Tokyo, Psychiatry, Tokyo, Japan

Background: The D-neuron, i.e. TAAR1 ligand neuron, has been described in the mammarian central nervous system since 1983, whereas, trace amine receptor was cloned in 2001. In humans, the D-neuron system in nucleus accumbens (D16), projection field of mesolimbic dopamine (DA) system, is far developed than even in non-human primate, monkeys. Our previous post-mortem brain studies have shown that in patients with chronic schizophrenia, the number of D-neurons in D16 reduced markedly. This finding, clinical observations and recent publications available on TAAR1 research lead to establish “D-cell hypothesis of schizophrenia” (Ikemoto K., Lancet, 2025). The hypothesis shows molecular mechanisms of mesolimbic DA hyperactivity and progressive pathognomonic procedures of schizophrenia, and indicates prospectiveness of TAAR1 medicinal chemistey, linking DA hypotheis and neural stem cell (NSC) dysfunction hypothesis of schizophrenia. However, recent research environment which emphasizes psychiatric molecular genetics has revealed unexpected difficulty in visualizing human D-neurons by using refined immunohistochemical technique. Repetitive disasters, including the Great East Japan Earthquake and COVID-19 pandemic, have also caused delay in D-neuron research.

Aims & Objectives: D-neuron pathology of schizophrenia had been performed by using post-mortem brains of schizophrenia, in most cases, of chronic or residual stages of aged individuals. Due to applying an improved aromatic L-amino acid decarboxylase (AADC) immunohistochemistry of ABC-DAB free-floating method, to paraformaldehyde (PFA)-fixad post-mortem brains, the number of post-mortem brains used for the previous studies has been limited. Re-establishment of the similar immunohistochemical research unit is actually no easy in the current circumstances in Japan. So, I re-examined D-neuron pathology in the D16 from presumable prodromal stage to chronic or residual stages of schizophrenia.

Method: I examined AADC-immunostained glass slide specimens (a study performed by approval of the Ethical Committee of National Minami Hanamaki Hospital, Japan (2001～2004), Ikemoto K. et al. Legal Medicine, 2003) detailly, by referring the previous and latest research findings, and literatures available on TAAR1, trace amines and schizophrenia research. Daily clinical observations on psychotic symptoms, such as paranoid-hallucinatory state, excitement, suicidal attempt, etc., of patients with mental illnesses were analyzed.

Results: In 27-year-old male, who died by suicide (jumping), D-neuron reduction was not noticed in the D16 of post-mortem brain obtained by pathological autopsy. In a legal antopsy middle-aged male case with schizophrenia, approximate 40% D-neuron reduction, compared with an age-, PMI-matched control, in D16 was observed. In pathological autopsy, aged patients with chronic schizophrenia, who died in hospitals, the number of D-neurons in D16 was markedly reduced. D16 D-neuron decrease in post-mortem brains of patients with schizophrenia, that I reported previouly, was confirmed. Aging-related D16 D-neuron degeneration was also suspected.

Discussion & Conclusions: Although, the mechanisms in D16 D-neuron decrease in post-mortem brains of schizophrenia have not yet been precisely clarified, dysfunction of subventricular and/or hippocampal NSC, inflammation, infection, degeneration, malnutrition, immune dysfunction, genetic deficits, etc, are possibly involved. The latest clinical trials in TAAR1 medicinal chemistry have shown no prompt effectiveness of TAAR1 agonists or TAAR1 partial agonists in improving schizophrenia symptoms, of which mechanisms remain still unclear. Further D-neuron research is pivotal in progress of TAAR1 medicinal chemistry.