Akiyoshi Nishimura

Detection of measles virus nucleoprotein mRNA in autopsied brain tissues.

By means of RT-PCR, a portion of measles virus (MV) mRNA encoding nucleoprotein (NP) could be detected in 11 (18%) of 61 brain tissue samples obtained from administrative autopsy cases, who apparently had not suffered from subacute sclerosing panencephalitis (SSPE)-like central nervous system disorders. Most of the brain-derived NP sequences showed significant asynonymous nucleotide substitutions when compared with wild-type MV isolates and SSPE virus. Our present results suggest that MV commonly persists in the human brain without causing apparent clinical symptoms, probably due to decreased virus replication.

Demonstration of l-dopa decarboxylating neurons specific to human striatum

In the human striatum, we immunohistochemically demonstrated many neurons that were immunoreactive for aromatic L-amino acid decarboxylase (AADC; the second step dopamine-synthesizing enzyme) but not for tyrosine hydroxylase (TH; the first step dopamine-synthesizing enzyme). The number of AADC-positive neurons was especially large in the ventral striatum including the nucleus accumbens. The significance of AADC-positive neurons are discussed in relation to the acting sites of L-dopa and antipsychotic drugs.

Does tyrosinase exist in neuromelanin-pigmented neurons in the human substantia nigra?

It is controversial whether tyrosinase is involved in the neuromelanin-biosynthetic pathway. We examined tyrosinase-immunoreactivity in human substantia nigra neurons which contain neuromelanin pigments, using antibodies against human tyrosinase and human tyrosine hydroxylase. In human melanoma, the antibody to tyrosinase showed intense immunoreactivity while there was no immunoreactivity with antibody to tyrosine hydroxylase. In the human midbrain pigmented neurons, however, we could detect no tyrosinase-immunoreactivity while the neurons were strongly immunoreactive to tyrosine hydroxylase. The present results suggest that tyrosinase is not involved in the main pathway of neuromelanin biosynthesis.

Human midbrain dopamine neurons express serotonin 2A receptor: an immunohistochemical demonstration.

We demonstrated intense serotonin (5-HT) 2A receptor immunoreactivity in the human ventral tegmental area (VTA) using by a recently raised antibody against 5-HT2A receptor. The substantia nigra (SN) neurons also showed 5-HT2A receptor immunoreactivity. Double immunohistochemistry of 5-HT2A receptor and tyrosine hydroxylase (TH) revealed many neurons doubly labeled by 5-HT2A receptor and TH in the VTA and SN. It is suggested that activity of human midbrain dopaminergic neurons might be strongly regulated via 5-HT2A receptors at the level of their originating nuclei.

Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls.

Several lines of evidence suggest that a partly genetically controlled serotonergic dysfunction is involved in the biological pathogenesis of suicide. In this study, we measured tryptophan hydroxylase (TPH) immunoreactivity as a pre-synaptic marker, and serotonin receptor 2A (5HT2A receptor) density as a post-synaptic marker in the serotonergic system in 10 postmortem brains of suicide victims. We also examined whether TPH gene polymorphisms (A218C and A-6526G polymorphisms) could affect TPH immunoreactivity and 5HT2A receptor gene polymorphism (A-1438G polymorphism) could affect 5HT2A receptor density in 28 postmortem brain samples. No significant differences were found in TPH immunoreactivity or 5HT2A receptor density between suicide victims and controls. The AA genotype of the A218C polymorphism of the TPH gene showed higher TPH immunoreactivity along with lower 5HT2A receptor density than did any other genotypes in the postmortem brains of both suicide victims and controls. Our findings suggest that the A218C polymorphism of the TPH gene can be expected to provide new insights not only for neurobiological studies of suicide, but also for research into the behavioral characteristics that may be associated with serotonergic dysfunction.

Serotonin 2A receptor gene polymorphism is not associated with completed suicide.

Several lines of evidence indicate that a serotonergic dysfunction is involved in the biological susceptibility to suicide. Recently, the A-1438G polymorphism of the serotonin 2A (5-HT2A) receptor gene has been suggested to be associated with suicide, but the results are inconsistent. We examined whether the A-1438G polymorphism of the 5-HT2A receptor gene was associated with suicide itself using 151 Japanese completed suicides. No significant difference in genotype distribution or allele frequencies of the polymorphism was found between the completed suicides and the comparison group. We conclude that the A-1438G polymorphism of the 5-HT2A receptor gene is not likely to have a major effect on the biological susceptibility of suicide.

Tyrosine hydroxylase and aromatic l-amino acid decarboxylase do not coexist in neurons in the human anterior cingulate cortex

Immunoreactivity for aromatic L-amino acid decarboxylase (AADC), the second step dopamine-synthesizing enzyme, was found immunohistochemically in neurons of the human anterior cingulate cortex (ACC). Most of these neurons were located in layers V and VI and subcortical white matter; a small number were occasionally found in layer III. Double immunohistochemistry for tyrosine hydroxylase (TH: the first step dopamine-synthesizing enzyme) and AADC revealed that no neuronal cell bodies in the ACC were doubly immunostained for TH and AADC, suggesting that these TH-only- or AADC-only-immunoreactive neurons were not dopaminergic. AADC neurons in the human ACC might transform L-DOPA to dopamine, droxidopa to noradrenaline, and/or 5-hydroxytryptophan to serotonin.

Do all of human midbrain tyrosine hydroxylase neurons synthesize dopamine

We examined whether all of human midbrain tyrosine hydroxylase (TH) neurons substantially synthesize dopamine (DA) using dual labeling immunohistochemical technique of TH and aromatic L-amino acid decarboxylase (AADC). In the substantia nigra, besides many neurons doubly stained for TH and AADC, neurons stained only for TH and only for AADC (D-neurons [C.B. Jaeger, D.A. Ruggiero, V.R. Albert, T.H. Joh, D.J. Reis, Immunocytochemical localization of aromatic l-amino acid decarboxylase, in: A. Björklund, T. Hökfelt (Eds.), Handbook of Chemical Neuroanatomy, Classical Transmitters in the CNS, Vol. 2, Part 1, Elsevier, Amsterdam, 1984, pp. 387-408.]) were identified. In the ventral tegmental area, dually labeled neurons and TH-only-positive neurons were found. It is indicated that the number of midbrain TH neurons does not reflect the exact number of DA neurons.

Tryptophan hydroxylase gene polymorphisms are not associated with suicide

Several lines of evidence suggest a serotonergic dysfunction involved in the biological susceptibility of suicide. Abnormalities of serotonergic markers such as 5-hydroxyindoleacetic acid and prolactin response to fenfluramine have been demonstrated in suicide subjects. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, is one of the most important regulating factors in the serotonergic system. Recently, polymorphisms of the TPH gene have been identified and some of these polymorphisms have been suggested to be associated with suicide, but the results are still inconsistent. We examined whether the -6526A/G polymorphism in the promoter region and the 218A/C polymorphism in intron 7 of the TPH gene were associated with suicide using 132 Japanese suicide victims. No significant difference in genotype distribution and allele frequencies of these polymorphisms was found between the suicide victims and the controls. We concluded neither the -6526A/G polymorphism nor the 218A/C polymorphism of the TPH gene is likely to have a major effect on the susceptibility of suicide. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:861-863, 2000.

Influence on the suicide rate two years after a devastating disaster: A report from the 1995 Great Hanshin-Awaji Earthquake

Aims:  The relationship between suicide and disaster is an important problem but its not clear. We conducted this study to determine whether a natural disaster affects suicide rates.