Akeo Kurumaji

Increases in strychnine-insensiive glycine binding sites in cerebral cortex of chronic schizophrenics: Evidence for glutamate hypothesis

Strychnine-insensitive glycine binding sites, an absolute requirement of the responses mediated by N-methyl-D-aspartate (NMDA) receptors, were measured in the postmortem brains of 13 chronic schizophrenics and 10 controls, using a radiolabeled receptor assay. Specific [3H]glycine binding was significantly increased in six of the 16 areas of the cerebral cortex that were investigated. Scatchard analysis performed in these areas showed a significant increase in the maximum number of binding sites, with no change in the affinity of binding. Multiple regression analysis confirmed that the increase was not due to age at death or interval from death to freezing. The increase was also observed in the off-drug cases of schizophrenics who had not taken antipsychotics for more than 40 days before death. These results suggest that the increases in NMDA-associated glycine binding sites, possibly ascribed to the postsynaptic compensation for impaired glutamatergic neurotransmission, might be implicated in the pathophysiology of schizophrenia.

Evidence for association of the myo -inositol monophosphatase 2 ( IMPA2 ) gene with schizophrenia in Japanese samples

In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. we determined its genomic structure and detected three new single nucleotide polymorphisms (snps). in the present study, we screened the gene further to search for additional polymorphisms in japanese samples and identified seven other snps, including a novel missense mutation. these polymorphisms clustered into three regions of the gene. three relatively informative snps, 58g>a, ivs1–15g>a and 800c>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031–0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese.

Excitatory amino acids: Implications for psychiatric disorders research

The hyperdopaminergic theory of schizophrenia may account for some types of schizophrenia, but schizophrenia with negative symptoms or resulting in a chronic state of deterioration after repeated relapses cannot be explained by this theory. This minireview first discusses the interactions between dopamine and excitatory amino acid (EAA) neurons to produce abnormal behavior. Secondly, it deals with the influence of the psychotropic drugs on EAA, such as the relationship between phencyclidine and the hypoglutamate theory, the involvement of EAA in behavioral sensitization induced by amphetamines, the interactions between antipsychotic, antidepressant and antianxiety drugs and EAA, considering the possibility of developing newer psychotropic drugs related with EAA. Finally, glutamate receptors measured in postmortem schizophrenic brains are tabulated and the bases of the hypoglutamate hypothesis are discussed.

Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler.

We introduced a new genotyping method, fluorescence resonance energy transfer-based melting curve analysis on the LightCycler, for the analysis of the gene, DUSP6 (dual specificity MAP kinase phosphatase 6), in affective disorder patients. The DUSP6 gene is located on chromosome 12q22–23, which overlaps one of the reported bipolar disorder susceptibility loci. because of its role in intracellular signalling pathways, the gene may be involved in the pathogenesis of affective disorders not only on the basis of its position but also of its function. we performed association analysis using a t>G polymorphism that gives rise to a missense mutation (Leu114Val). No evidence for a significant disease-causing effect was found in Japanese unipolars (n = 132) and bipolars (n = 122), when compared with controls (n = 299). More importantly, this study demonstrates that melting curve analysis on the LightCycler is an accurate, rapid and robust method for discriminating genotypes from biallelic markers. This strategy has the potential for use in high throughput scanning for and genotyping of single nucleotide polymorphisms (SNPs).

An increase in [3H] CGS21680 binding in the striatum of postmortem brains of chronic schizophrenics

We measured adenosine 2a receptors in basal ganglia of 13 schizophrenics and 10 controls, using [3H] CGS21680 as a ligand for the receptor binding assay. There was a significant increase in the specific [3H] CGS21680 binding in the putamen and caudate, but not in the globus pallidus of externa, of the schizophrenic patients, compared to those of controls. These results provide evidence suggesting that adenosine 2a receptors play a role in the pathophysiology of schizophrenia.

Decreases in peripheral-type benzodiazepine receptors in postmortem brains of chronic schizophrenics

SummaryWe measured the peripheral-type benzodiazepine receptors (PBRs), a marker of gliosis, in 26 brain areas (cerebral cortex, thalamus and extrapyramidal system) of the postmortem brains of 13 chronic schizophrenics and 10 controls, using [3H] PK 11195 as a ligand for the receptor assay. The specific [3H] PK 11195 binding was significantly decreased in three brain areas (superior parietal cortex, primary visual area and putamen) of schizophrenics, although there were no changes in the binding in the other brain areas. Scatchard analysis revealed that there were decreases in both the Bmax and Kd of [3H] PK 11195 binding in the brain areas. These results were almost in accordance with a number of neuropathological studies reporting that there was no change or reduction in glial cells in the brain regions of schizophrenics and suggested that the decreased density of PBRs in the brain may be involved in the pathophysiology of schizophrenia, associated with reduced production of neurosteroids coupled to PBRs.

α‐[3H]Amino‐3‐Hydroxy‐5‐Methylisoxazole‐4‐Propionic Acid Binding to Human Cerebral Cortical Membranes: Minimal Changes in Postmortem Brains of Chronic Schizophrenics

Abstract: The binding of α‐[3H]amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid ([3H]AMPA), a selective ligand for the ion channel‐linked quisqualate receptor, was evaluated in Triton X‐100‐treated membranes of human cerebral cortex. The presence of chaotropic ions produced divergent effects on specific [3H]AMPA binding: A twofold increase in the binding was observed with thiocyanide at 100 mM, although iodide (100 mM) and perchlorate (100 mM) reduced the binding. Chemical modifications of the sulfhydryl group with p‐chloromercuriphenylsulfonic acid (PCMBS) produced threefold increases in specific [3H]‐AMPA binding in the absence of KSCN as well as in the presence of KSCN. Treatment with dithiothreitol restored the enhanced specific [3H]AMPA binding by PCMBS to the basal level. Although specific [3H]AMPA binding in the absence of KSCN showed a single site (KD= 220 nM, Bmax= 235 fmol/mg of protein), curvilinear Scatchard plots of, specific [3H]AMPA binding in the presence of 100 mM KSCN can be resolved into two binding sites with the following parameters: KDI= 5.82 nM, Bmaxx= 247 fmol/mg of protein; KD2= 214 nM, Bmax2= 424 fmol/mg of protein. Quisqualate and AMPA were the most potent inhibitors of the [3H]AMPA binding in the presence of KSCN. Potent inhibitors of the binding included β‐N‐oxalylamino‐l‐alanine (l‐BOAA), cysteine‐S‐sulfate, l‐glutamate, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione, and 6,7‐dinitroquinoxaline‐2,3‐dione. Kainate, l‐homocysteine sulfinic acid, and l‐homocysteic acid were active with an IC50 value of a micromolar concentration, whereas l‐cysteic acid and l‐cysteine sulfinic acid were weakly active. N‐Methyl‐d‐aspartate, l‐aspartate, N‐acetylaspartylglutamate, quinolinate, and 1‐naphthylacetyl spermine, an analogue of Joro spider toxin, were inactive at 1 mM. These results suggest that l‐glutamate has an important effect on AMPA receptors in the human cerebral cortex and that l‐BOAA and cysteine‐S‐sulfate exhibit their neurotoxicity through AMPA receptors. Specific [3H]AMPA binding, using the ligand at 6 nM, in the presence of 100 mM KSCN exhibited a heterogeneous distribution pattern in the human cerebral cortex: [3H]AMPA binding values were high in the frontal and occipital cortex, whereas they were low in the parietotemporal cortex. However, no statistically significant changes in [3H]AMPA binding were observed in 22 brain areas of the cerebral cortex of chronic schizophrenics, compared with controls, suggesting that AMPA receptors in the cerebral cortex are minimally involved in an abnormality of excitatory amino acidergic neurons hypothesized in schizophrenic brain.

White Matter Abnormalities as a Risk Factor for Postoperative Delirium Revealed by Diffusion Tensor Imaging

OBJECTIVE Delirium is a common and critical clinical syndrome in older persons. The authors examined whether any abnormalities in the white matter (WM) assessed by diffusion tensor imaging (DTI) predisposes patients to develop delirium after cardiac surgery and also analyzed other risk factors for delirium. METHOD In 116 consecutive patients who underwent scheduled cardiac operations, fractional anisotropy (FA) values obtained by DTI before the surgery and pre-, peri-, and postoperative factors were evaluated. The postoperative delirium was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for delirium. RESULTS Delirium developed in 19 of 116 patients (16.4%). Eighteen of the patients with delirium (94.7%) were older than 60 years. A multivariate logistic regression analysis showed that advanced age and poor performance on a semantic fluency task (the Word Fluency test animal) were important predictive indicators of the delirium. In addition, a voxel-by-voxel analysis using the Statistical Parametrical Mapping 2 revealed that the FA values of the patients with postoperative delirium were significantly lower than those of the nondelirium patients in the bilaterally widespread deep WMs and bilateral thalamus, whereas the analysis treating age as a nuisance variable indicated a significant change in only four clusters of the brain areas, e.g., the left frontal lobe WM, and left thalamus, when compared with the nondelirium group. CONCLUSION The abnormalities in the deep WMs and thalamus that were mainly accelerated by aging may account for the vulnerability to postoperative delirium, and the semantic word fluency could be a useful predictive indicator of delirium.

Cold and immobilization stress-induced changes in pain responsiveness and brain met-enkephalin-like immunoreactivity in the rat

Pain responsiveness and Met-enkephalin-like immunoreactivity (MLI) were studied in the rat after cold (25 degrees C) and immobilization stress for different lengths of time (30 min, 90 min and 180 min). The 30-min stress-induced analgesia (as measured by the tail-flick method), which was partially antagonized by pretreatment with naloxone (5 mg/kg, SC), and the magnitude of this analgesia was less than that of the 90-min stress or 180-min stress. The 30-min stress resulted in a significant decrease in MLI in the mesolimbic area, striatum, hypothalamus and thalamus. After the 90-min stress, MLI was found to be significantly decreased in the prefrontal cortex, amygdaloid nuclei and piriform cortex, thalamus and hippocampus, while the 180-min stress failed to induce a significant change in any brain area tested. As such a change in MLI content was thought to be related to an increase in the activity of the endogenous Met-enkephalin neuronal system, the activation of this system by the stress, especially in the hypothalamus and thalamus, seemed to be associated with analgesia.

An association study between polymorphisms of L1CAM gene and schizophrenia in a Japanese sample

L1CAM, a neural cell adhesion molecule, plays an important role in the development of the central nervous system. The human L1CAM gene is located in Xq28. Mutations in the gene are responsible for a wide spectrum of neurological abnormalities and mental retardation. Schizophrenia may result from early neurodevelopmental abnormalities. We screened 30 male and 30 female schizophrenic patients for their genomic sequence of the L1CAM gene in order to determine the DNA sequence variations. Three novel variations located in exon 18 (10564 G > A, GG/AA at codon 758), intron 11 (8575 A > C), and intron 25 (13504 C > T) were detected. An association study of the identified polymorphisms was then performed in a Japanese sample of 152 male and 115 female patients with schizophrenia and 121 male and 114 female control subjects. A statistically significant increase in the count of the 13504 T-allele was observed in the male patients, compared to the male controls, with no differences in the variations of exon 18 or intron 11. There was no statistically significant change in the distribution of allele or genotype of any variations in the female schizophrenics, in comparison with the female controls. These results suggest that the polymorphism in intron 25 plays a role in the genetic predisposition of male schizophrenia in the Japanese sample.