Yohtaro Numachi

Genomewide High-Density SNP Linkage Analysis of 236 Japanese Families Supports the Existence of Schizophrenia Susceptibility Loci on Chromosomes 1p, 14q, and 20p

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

Norepinephrine Transporter Blockade can Normalize the Prepulse Inhibition Deficits Found in Dopamine Transporter Knockout Mice

Dopamine transporter knockout (DAT KO) mice display deficits in sensorimotor gating that are manifested by reduced prepulse inhibition (PPI) of the acoustic startle reflex. Since PPI deficits may model some of the cognitive dysfunctions identified in certain neuropsychiatric patients, we have studied the effects of transporter blockers on PPI in wild-type and DAT KO mice. Treatments with High dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters (60 mg/kg cocaine or methylphenidate) significantly impaired PPI in wild-type mice. By contrast, these treatments significantly ameliorated the PPI deficits observed in untreated DAT KO mice. In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine (10 or 30 mg/kg) also significantly reversed PPI deficits in DAT KO mice. By contrast, while the SERT inhibitor fluoxetine (30 mg/kg) normalized these PPI deficits in DAT KO mice, citalopram (30 or 100 mg/kg) failed to do so. The ‘paradoxical’ effects of cocaine and methylphenidate in DAT KO mice are thus likely to be mediated, at least in part by the ability of these drugs to block NET, although serotonin systems may also have some role. Together with recent microdialysis data, these results support the hypothesis that prefrontal cortical NET blockade and consequent enhancement of prefrontal cortical extracellular dopamine mediates the reversal of PPI deficits in DAT KO mice.

Methamphetamine alters expression of DNA methyltransferase 1 mRNA in rat brain.

Methamphetamine, a potent and indirect dopaminergic agonist, also increases glucocorticoid hormone secretion. Glucocorticoid hormones facilitate behavioral effects of methamphetamine in rodents. Several reports suggest that glucocorticoid hormones modulate expression of DNA (cytosine-5-)-methyltransferase 1 (Dnmt1). Dnmt1 was originally recognized as being involved in DNA replication, but a recent study found high levels of Dnmt1 in rodent brains, suggesting a neuron-specific unknown function of Dnmt1. In the present study, we found subchronic methamphetamine treatment (4 mg/kg, i.p., once daily for 21 days) to induce different patterns of Dnmt1 mRNA expression in the nucleus caudatus and nucleus accumbens of two inbred rat strains, Fischer 344/N (increased Dnmt1) and Lewis/N (decreased Dnmt1). These patterns paralleled methamphetamine-induced striatal glucocorticoid receptor mRNA in these two rat strains in our previous study. Because Fischer rats have a hyperresponsive negative feedback in their hypothalamic-pituitary-adrenocortical (HPA) axis and thus a shorter duration corticosterone response to subchronic methamphetamine treatment, they were resistant to sensitizing effects of methamphetamine and their glucocorticoid receptor mRNA levels were upregulated. Lewis rats which have a hyporesponsive feedback in their HPA axis and a longer duration of corticosterone secretion with subchronic methamphetamine were prone to methamphetamine sensitization and their striatal glucocorticoid receptor mRNA levels were downregulated. Our present data suggest that methamphetamine results in differential DNA methylation as well as gene expression in the nucleus caudatus and nucleus accumbens of F344 and Lewis rats. Methamphetamine-induced differences in gene expression might be related to the contrasting susceptibilities of these rats to behavioral and neurochemical effects of methamphetamine.

Psychostimulant Alters Expression of DNA Methyltransferase mRNA in the Rat Brain

Abstract: Methamphetamine (MAP), the most frequently abused substance in Japan, causes severe drug dependence and psychosis, similar to schizophrenia. It is suggested that long‐term alterations in gene expression is related to MAP‐induced brain dysfunction, including dependence and psychosis. DNA (cytosine‐5) methyltransferase (Dnmt), a methylating enzyme of cytosine residues on CpG‐dinucleotides, plays an important role in X chromosome inactivation, genomic imprinting, and gene expression. Reelin is an extracellular matrix protein secreted by GABAergic interneurons. Heterozygous reeler mice that exhibit a 50% downregulation of reelin expression replicate the dendritic spine and GABAergic defects described in schizophrenia. DNA methylation plays an important role in the epigenetic modification of reelin expression. We previously found that MAP could alter expression of Dnmt1 mRNA in the rat brain. In this study, we examined the brain mRNA for Dnmt2 and reelin in MAP‐treated Wistar rats. Acute MAP (4 mg/kg) treatment significantly decreased Dnmt2 mRNA by 27% to 39% in hippocampus dentate gyrus, CA1, and CA3 24 h after treatment, and significantly decreased reelin mRNA by 28% in frontal cortex 3 h after treatment. These results suggest that (1) MAP can alter DNA methylation as well as expression of genes in these brain regions, and (2) decrease in reelin mRNA in the frontal cortex is similar to heterozygous reeler mice, which might be related to schizophrenia‐like psychotic symptoms of MAP psychosis.

Visual event‐related potential in mild dementia of the Alzheimer's type

Abstract Visual event‐related potentials (ERP) and behavioral measures were recorded during a geometrical‐figure discrimination task to examine sensory processing in 10 patients with mild dementia of the Alzheimers type (DAT) and 10 age‐matched controls. No difference existed between the groups in P1, N1, and P2 potentials, which reflects the early stage of sensory processing, as well as in NA potential, which reflects pattern recognition. The patients showed reduced amplitude of P3 potential, retarded reaction time, and increased behavioral errors compared to controls. These findings suggest that the patients with mild DAT were intact in early sensory processing including pattern recognition but were selectively compromised in higher‐level processing, including integration of information and memory matching, which may influence behavioral deviation.

Lack of repetition priming effect on visual event-related potentials in schizophrenia.

BACKGROUND The present study was designed to assess, using event-related potentials, whether aberrant semantic processing reported in schizophrenia results from primary semantic overactivation or contextual dysregulation. METHODS The visual event-related brain potentials were compared between 9 schizophrenic subjects and 16 normal control subjects performing two kinds of semantic categorization tasks with different nontarget stimuli: 1) nontargets comprising words, pseudowords, and unpronounceable foreign letters and 2) nontargets comprising initial presenting words, immediate repetition words, and delayed repetition words. RESULTS Schizophrenic subjects showed no evidence suggestive of a greater negative potential associated with words and pseudowords, but they did show a lack of amplitude change associated with immediately repeated words relative to that in control subjects. CONCLUSIONS These results suggest that aberrant semantic activation in schizophrenia results mainly from a failure to utilize information from preceding words or context, and could explain the increased N400 to the congruent or related words recently reported in this disease.

Reduced tumor growth in a mouse model of schizophrenia, lacking the dopamine transporter

The incidence of cancer in patients with schizophrenia has been reported to be lower that in the general population. On the other hand, it is well established that patients with schizophrenia have a hyper‐dopaminergic system and dopamine has the ability to inhibit tumor angiogenesis. Therefore, in order to investigate the molecular mechanisms responsible for the lower cancer risk in schizophrenic patients, we used a mouse model of schizophrenia, which shows hyper‐dopaminergic transmission in the nerve terminals of dopaminergic neurons. Here, we hypothesized that tumor growth was reduced in a mouse model of schizophrenia, lacking the dopamine transporter (DAT), and investigated tumor growth and angiogenesis in DAT knockout mice. The subcutaneous tumor in mice inoculated with cancer cells was smaller in DAT−/− mice than in the wild type (p < 0.05); however, the level of plasma dopamine in DAT−/− mice was lower than that of control littermates. Using human umbilical vascular endothelial cells (HUVEC), we examined dopamine signaling through dopamine D1 receptor (D1R) and D2R. Dopamine stimulation slightly decreased the surface expression of vascular endothelial growth factor receptor‐2 (VEGF‐R2) but induced the phosphorylation of VEGF‐R2 through Src in HUVEC. In addition, DAT−/− mice had less D1R. Both pharmacological and genetic interruption of D1R showed inhibited tumor growth. These results suggest that modulation of the dopaminergic system may contribute to cancer therapy.

The role of cognitive-motor function in precipitation and inhibition of epileptic seizures.

Summary:  Purpose: To examine the effects of cognitive–motor function on EEG discharges and the neuropsychological mechanisms of seizure induction in patients sensitive to cognitive–motor tasks.

Impaired cliff avoidance reaction in dopamine transporter knockout mice

RationaleImpulsivity is a key feature of disorders that include attention-deficit/hyperactivity disorder (ADHD). The cliff avoidance reaction (CAR) assesses maladaptive impulsive rodent behavior. Dopamine transporter knockout (DAT-KO) mice display features of ADHD and are candidates in which to test other impulsive phenotypes.ObjectivesImpulsivity of DAT-KO mice was assessed in the CAR paradigm. For comparison, attentional deficits were also assessed in prepulse inhibition (PPI) in which DAT-KO mice have been shown to exhibit impaired sensorimotor gating.ResultsDAT-KO mice exhibited a profound CAR impairment compared to wild-type (WT) mice. As expected, DAT-KO mice showed PPI deficits compared to WT mice. Furthermore, the DAT-KO mice with the most impaired CAR exhibited the most severe PPI deficits. Treatment with methylphenidate or nisoxetine ameliorated CAR impairments in DAT-KO mice.ConclusionThese results suggest that DAT-KO mice exhibit impulsive CAR behavior that correlates with their PPI deficits. Blockade of monoamine transporters, especially the norepinephrine transporter (NET) in the prefrontal cortex (PFC), may contribute to pharmacological improvement of impulsivity in these mice.

Hyperthermic and lethal effects of methamphetamine: roles of dopamine D1 and D2 receptors.

Both human and animal studies suggest that hyperthermia contributes to the lethal effects of methamphetamine. To elucidate the roles of dopamine D1 and D2 receptors in methamphetamine-induced hyperthermia and lethal effects, we used D1 knockout (D1KO) mice, D2 knockout (D2KO) mice, and wild-type littermates. After the administration (i.p.) of a single dose of 30 mg/kg methamphetamine, no hyperthermic effect on body temperature was observed in D2KO mice, though there was a slight elevation in D1KO mice and a marked elevation in wild-type mice. Approximately 27% of the wild-type mice died after the administration, compared to only 7% of D1KO mice and 4% of D2KO mice. In conclusion, both D1 and D2 receptors play roles in the lethal toxic effects of methamphetamine, and mainly the D2 receptor is involved in the elevation of body temperature.