Kiyoshi Maeda

Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients.

Previous neuropathological studies have revealed that the corticolimbic system of schizophrenic patients expresses abnormal levels of various synaptic molecules, which are known to be influenced by the neuronal differentiation factors, neurotrophins. Therefore, we determined levels of neurotrophins and their receptors in the postmortem brains of schizophrenic patients and control subjects in relation to molecular impairments in schizophrenia. Among the neurotrophins examined, levels of brain-derived neurotrophic factor (BDNF) were elevated specifically in the anterior cingulate cortex and hippocampus of schizophrenic patients, but levels of nerve growth factors and neurotrophin-3 showed no change in any of the regions examined. In parallel, the expressions of TrkB receptor and calbindin-D, which are both influenced by BDNF, were reduced significantly in the hippocampus or the prefrontal cortex. However, neuroleptic treatment did not appear to mimic the neurotrophic change. Neither withdrawal of drug treatment in patients nor chronic administration of haloperidol to rats altered levels of BDNF. These findings suggest that neurotrophic abnormality is associated with the corticolimbic structures of schizophrenic patients and might provide the molecular substrate for pathological manifestations of the illness.

Expression of apolipoprotein E mRNA in rat microglia

Apolipoprotein E (apoE) is a major risk factor for Alzheimer disease (AD), which is the most common cause of progressive dementing illness. ApoE has been postulated to be synthesized by astrocytes and taken up by microglia and neuronal cells. However, it remains unknown whether apoE is also produced by microglia in the brain. We analyzed apoE mRNA expression of microglia using a rat primary culture system. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed expression of apoE mRNA in cultured rat microglia. By RT-in situ-PCR, microglia showed positive staining for the PCR product of apoE mRNA. These results indicated that apoE was biosynthesized in rat microglia. We suggest that microglia might be one of the sources of apoE in the brain, and that apoE synthesized in microglia might be closely related to the pathogenesis of AD.

Selective reduction of a PDZ protein, SAP-97, in the prefrontal cortex of patients with chronic schizophrenia

Many postsynaptic density proteins carrying postsynaptic density‐95/discs large/zone occludens‐1 (PDZ) domain(s) interact with glutamate receptors to control receptor dynamics and synaptic plasticity. Here we examined the expression of PDZ proteins, synapse‐associated protein (SAP) 97, postsynaptic density (PSD)‐95, chapsyn‐110, GRIP1 and SAP102, in post‐mortem brains of schizophrenic patients and control subjects, and evaluated their contribution to schizophrenic pathology. Among these PDZ proteins, SAP97 exhibited the most marked change: SAP97 protein levels were decreased to less than half that of the control levels specifically in the prefrontal cortex of schizophrenic patients. In parallel, its binding partner, GluR1, similarly decreased in the same brain region. The correlation between SAP97 and GluR1 levels in control subjects was, however, altered in schizophrenic patients. SAP102 levels were also significantly reduced in the hippocampus of schizophrenic patients, but this reduction was correlated with sample storage time and post‐mortem interval. There were no changes in the levels of the other PDZ proteins in any of the regions examined. In addition, neuroleptic treatment failed to mimic the SAP97 change. These findings suggest that a phenotypic loss of SAP97 is associated with the postsynaptic impairment in prefrontal excitatory circuits of schizophrenic patients.

ELEVATED URINARY FREE CORTISOL IN PATIENTS WITH DEMENTIA

Urinary free cortisol (UFC), 17-hydroxycorticosteroids (17-OHCS) in urine and dexamethasone suppression test (DST) were examined in patients with dementia of Alzheimer type (DAT) and multi-infarct dementia (MID), and nondemented elderly. Eight of 19 patients (42.1%) were DST nonsuppressor. UFC was significantly elevated in patients with dementia, compared with that in nondemented elderly. There was no difference in UFC levels between DAT and MID. The UFC level correlated with post-DST plasma cortisol level at 1600 in demented patients. The mean level of 17-OHCS in demented patients was increased, although the difference was not significant statistically. In demented patients, UFC levels, not 17-OHCS levels in urine were correlated with Mini-Mental State Examination scores. These results suggest that a hypothalamo-pituitary-adrenal axis function is activated in demented patients and that this activation relates generally to dementation itself, not to an etiology of dementia. Measurement of UFC might be a biological marker of dementia and may have a value in diagnosis of dementia.

Association between Catechol-O-Methyltransferase Functional Polymorphism and Male Suicide Completers

Suicide has been suggested to involve catecholaminergic dysfunction and to be related to genetics. Catechol-O-methyltransferase (COMT) 158Val/Met polymorphism (GenBank Accession No. Z26491) is a polymorphism of the gene encoding COMT, a major enzyme in catecholamine inactivation. The COMT 158Val/Met polymorphism affects COMT activity, that is, the alleles encoding Val and Met are associated with relatively high and relatively low COMT activity, respectively. In this study, we hypothesized that the COMT 158Val/Met polymorphism is associated with suicide. The study population consisted of 163 suicide completers (112 males and 51 females). We found that the genotype distribution of the COMT 158Val/Met polymorphism was significantly different between male suicide completers and male controls (p=0.036), while the frequency of the Val/Val genotype, a high-activity COMT genotype, was significantly less in male suicide completers than in male controls (OR: 0.52; 95% CL: 0.31–0.89; p=0.016). However, this was not the case in females. Our results suggest that the Val/Val genotype is a protective factor against suicide in males.

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.

MULTI-CENTER STUDY OF SEASONAL AFFECTIVE DISORDERS IN JAPAN : A PRELIMINARY REPORT

A multi-center study on seasonal affective disorder (SAD) was conducted from the autumn of 1988 to the spring of 1989 with the cooperation of 16 facilities in Japan. Forty-six SAD patients were identified among 1104 respondents to our advertisements in mass media, or patients seen at the outpatient clinics. Essentially similar findings to other previous reports were obtained in terms of onset age of the first episode, duration of episode, high proportion of depression in first-degree relatives and atypical vegetative symptoms. However, a nearly equal sex ratio, together with a high proportion of unipolar depression, is characteristic of the present study. Increased appetite and carbohydrate craving were predominant only in female patients, whereas hypersomnia was prominent in both sexes. Effective response to light therapy was found in 17 SAD patients. However, a controlled study on a large number of patients is required to allow final conclusions on the efficacy of light therapy in Japanese SAD patients.

Age-related changes in the brains of senescence-accelerated mice (SAM): Association with glial and endothelial reactions

Twelve substrains of inbred senescence‐accelerated mice (SAM) have been developed, among which the SAMP8 and SAMP10 strains show a significant age‐related deterioration in learning and memory for passive and active avoidance tasks. These strains have, respectively, a low and high incidence of systemic senile amyloidosis. Although we found no amyloid deposits in their brain parenchyma, a variety of age‐related alterations were identified, involving neurons, glia, and vessels in the brain tissues. Here we review the degenerative changes in aged SAMP8 and SAMP10 brains. These changes are generally similar to the pathology of aging human brain and may be characterized by their association with some specific glial reactions. Microsc. Res. Tech. 43:59–67, 1998.

Effect of serotonergic agents on regional concentrations of somatostatin- and neuropeptide Y-like immunoreactivities in rat brain

A possible role for neuropeptides in affective disorders is suggested by many investigators. Somatostatin-like immunoreactivity (SS-LI) and neuropeptide Y-like immunoreactivity (NPY-LI) concentrations are demonstrated to be reduced in cerebrospinal fluid from depressed patients. We have shown that long-term treatment with serotonin uptake inhibitors, clomipramine and zimelidine, reduce brain SS-LI concentrations in the rat. We have studied the effect of serotonergic agents on regional brain SS-LI and NPY-LI concentrations in rats. Long-term treatment with 5-hydroxytryptamine (5-HTP), a serotonin precursor, caused reductions in SS- and NPY-LI levels in the hypothalamus. SS- and NPY-LI concentrations in the brain were markedly elevated by treatment with p-chlorophenylalanine, a serotonin synthesis inhibitor. Intracerebroventricular administration of 5,7-dihydroxytryptamine, a serotonin neurotoxin, resulted in elevations of both peptides in the brain. These results suggest a inhibitory role for the serotonergic system in the brain in the regulation of SS and NPY.