A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet beta-cells and neurons.

Expression of drebrin E in migrating neuroblasts in adult rat brain: coincidence between drebrin E disappearance from cell body and cessation of migration.

Migrating neuroblasts in the adult brain form the rostral migratory stream (RMS) from the lateral ventricle to the olfactory bulb (OB) and then differentiate in the OB. In this study, we immunohistochemically analyzed drebrin expression in the RMS of the adult rat brain. Although drebrin is concentrated in dendritic spines of mature neurons, drebrin-immunopositive (DIP) cell bodies were observed in the RMS. The polysialated form of a neural cell adhesion molecule (PSA-NCAM) was detected in DIP cells. K(i)-67, a marker of proliferating cells, was also detected in a subset of DIP cells; however, neither glial fibrillary acidic protein, nestin nor vimentin was detected in DIP cells. These results indicate that DIP cells in the RMS are migrating neuroblasts. An image subtraction method, based on using anti-pan-drebrin and anti-drebrin A antibodies, demonstrated that DIP migrating neuroblasts are immunopositive for drebrin E but not for drebrin A (E+A-). Furthermore, olfactory bulbectomy increased the number of cells with drebrin E+A- signals in the RMS, indicating that these cells migrate along the RMS. Drebrin E+A- cells were also found in the subgranular layer of the dentate gyrus and in the piriform cortex. Thus, detection of drebrin E+A- signals is useful for identifying migrating neuroblasts in the adult brain. In the OB, drebrin E+A- signals were observed in the cell bodies of migrating neuroblasts in the core region; however, only fibrous and punctate drebrin E+A- signals were observed in postmigratory neuroblasts at the outer layers. These data demonstrate that the disappearance of drebrin E+A- signals from the cell body coincides with the cessation of neuronal migration. The disappearance of drebrin E from the cell body may be a molecular switch for the cessation of migration in newly generated neuroblasts.

Relationship between age at onset and magnetic resonance image-defined hyperintensities in mood disorders.

OBJECTIVES: To examine in patients with mood disorders the relationship of age at onset with the location and degree of MRI-defined brain hyperintensities. METHOD: Fifty-two patients diagnosed as having mood disorders and 14 controls participated in the study. Brain MR images were analyzed according to semiquantitative ratings for the anatomical distribution and severity of T2-weighted hyperintensities. We compared these hyperintensities among the three age- and sex-matched groups of late-onset mood disorder patients (LOM), early-onset mood disorder patients (EOM), and controls. The time since the onset of disorder was significantly longer in the EOM than in the LOM group. We also conducted linear multiple regression analysis using the severity of hyperintensities as dependent variable to determine whether the clinical features correlate with vascular pathology. RESULTS: As for deep white matter hyperintensity (DWMH), LOM exhibited higher ratings than EOM; as for brain areas, significant between-group differences were detected in the bilateral frontal areas and in the left parieto-occipital area. No significant difference was observed between EOM and controls. As for periventricular hyperintensity, there was no difference among the three groups. We obtained a significant regression model to predict DWMH ratings; age, number of ECTs, and LOM were selected as significant variables. CONCLUSION: The present study suggests that the time since the onset of disorder does not affect the development of white matter lesions, but that white matter lesions are associated with late-onset mood disorders. The frontal areas and the left parieto-occipital area would be important for the development of late-onset mood disorders.

Brain metabolic changes associated with predispotion to onset of major depressive disorder and adjustment disorder in cancer patients--a preliminary PET study.

OBJECTIVES: To explore neurobiological risk factors for major depressive disorder (MDD) and adjustment disorder in cancer patients by examining regional brain metabolism before psychiatric manifestation using positron emission tomography and by prospectively observing depressive and anxiety symptoms. METHOD: Cancer patients who showed no psychiatric symptoms when they underwent 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) were followed up for one year using the Hospital Anxiety and Depression Scale (HADS). Fourteen patients who showed high HADS scores and 14 patients who showed low HADS scores were assessed by a psychiatrist 2 years after the PET scan and grouped into the deterioration group (n=10) and the no-change group (n=9). 18F-FDG PET images were analyzed to examine the difference in local brain glucose metabolism between the two groups. RESULTS: The deterioration group showed a decreased glucose metabolism in the right medial frontal gyrus (BA6) and an increased glucose metabolism in the right posterior cingulate (BA29), right anterior cingulate (BA25), left subcallosal gyrus (BA25), and left caudate compared with the no-change group. CONCLUSION: Cancer patients who later developed MDD or adjustment disorder showed regional brain metabolic changes. These regions may be associated with vulnerability to the onset of MDD or adjustment disorder in cancer patients.

Cerebral blood volume changes in patients with eating disorders during word fluency: a preliminary study using multi-channel near infrared spectroscopy.

OBJECTIVE: This study investigated the characteristics of cerebral oxygenation changes in eating disorders patients (ED) and normal controls during the cognitive tasks, using a highly time-resolved, and non-invasive instrument. METHOD: Eleven female patients with anorexia nervosa or bulimia nervosa were recruited, and 11 healthy females participated. The relative concentrations of oxy-hemoglobin [o-Hb] and deoxy-hemoglobin [d-Hb] were measured during word fluency task using multichannel near infrared spectroscopy (NIRS). RESULTS: The increases of o-Hb and d-Hb during the task were compared between the groups. ED patients showed lower activation and a gradual increase in o-HB during the task. In the frontal, d-HB concentrations decreased during the task in ED patients. CONCLUSION: These specific patterns of oxygenation changes may indicate less supply and less demand of cerebral blood volume. Bedside measurements of cerebral oxygenation changes using NIRS are useful on understanding of neurophysiological features of ED.

Plasma des-acyl and acyl ghrelin in patients with eating disorders.

A recently recognized peptide, ghrelin, increases appetite and energy retention in human. Previous reports have shown higher plasma level in eating disorder (ED) patients and correlations with body mass index (BMI). This study examined these findings by measuring active (N-RIA) and total (C-RIA) levels of plasma ghrelin. Multipurpose assessments of symptoms were conducted for 11 ED patients and 5 control females. Results revealed significant differences of C-RIA between the groups. The BMI did not correlate with ghrelin, but demonstrated reversal correlation with the ratio of N-RIA and C-RIA (NC ratio) according to the ED or control group. The NC ratio also tended to be associated with a self-rating score. The NC ratio might be related to specific characteristics of ghrelin secretion or clearance in ED patients. Further basic and clinical investigations are necessary.

Structure of the Drosophila melanogaster gene encoding cyclin A.

A P element (PE)-induced Drosophila melanogaster mutation, hari, affects the formation of the bristle mechanosensory organ in the adult fly. In this mutation, the site of PE insertion is in the first intron of the gene (CycA) encoding cyclin A (CycA). In order to analyze the hari mutant at the molecular level, we cloned and sequenced the cDNA and genomic DNA encoding CycA. CycA has seven exons and six introns, and its transcription unit spans 6 kb. All exon-intron junctions are compatible with the GT/AG consensus. Results of primer extension analysis and RNase protection assay indicate that CycA has major and minor transcription start points (tsp). To our knowledge, this is the first report on the CycA genomic sequence from a multicellular organism.

18F alpha-methyl tyrosine PET studies in patients with brain tumors.

UNLABELLED: We have developed 18F-labeled alpha-methyl tyrosine (FMT) for PET imaging. The aim of this study was to evaluate the clinical application potential of FMT for patients with brain tumors. METHODS: Eleven healthy volunteers and 20 patients with brain tumors were injected with 185 MBq (5 mCi) FMT. In 3 healthy volunteers, whole-body imaging and urinary and plasma analysis were conducted for the assessment of the biodistribution of FMT. The normal range of cortical standardized uptake value (SUV) as a reference for comparing tumor SUV of FMT was estimated by using PET data obtained at 30 min postinjection in 8 healthy volunteers. Dynamic PET scans were conducted for 100 min in 4 healthy volunteers and for 30 min in 15 patients with brain tumors. The 10-min static images in another 4 volunteers and all patients were obtained at 30 min postinjection. In 13 patients, FMT uptake in the brain tumor was compared with 18F-fluorodeoxyglucose (FDG). Tumor-to-normal cortex count (T/N) ratio and tumor-to-white matter count (T/W) ratio and SUVs of brain tumors were determined on FMT and FDG PET images. RESULTS: Approximately 1480 MBq (40 mCi) FMT were produced in one radiosynthesis. Percentage injected dose (%ID) of FMT in the brain ranged from 2.8% to 4.9%, and approximately 50%ID of FMT was excreted in urine during 60 min postinjection, of which 86.6% was unmetabolized FMT. A faint physiological brain uptake with SUV of 1.61 +/- 0.32 (mean +/- SD, n = 8) was observed in healthy volunteers. Tumor SUV of FMT ranged from 1.2 to 8.2, with mean value of 2.83 +/- 1.57 (n = 23), which was significantly higher than that of the cortical area in healthy volunteers (P < 0.01). T/N and T/W ratios of FMT were significantly higher than those of FDG (2.53 +/- 1.31 versus 1.32 +/- 1.46, P < 0.001; 3.99 +/- 2.10 versus 1.39 +/- 0.65, P < 0.0001, respectively). CONCLUSION: FMT, like other radiolabeled amino acids, can provide high-contrast PET images of brain tumors.

Influence of pimozide on hypothalamo-pituitary function in children with behavioral disorders.

Hypothalamo-pituitary functions were examined in thirteen children with behavioral disorders (six with hyperkinesia, four with autism, two with tic and one with schizophrenia) before and during treatment with pimozide, an antidopaminergic drug. The mean (+/- S.E.M.) basal serum PRL level (24.5 +/- 4.2 ng/ml) during pimozide treatment was significantly higher than that (12.4 +/- 3.2 ng/ml) before treatment. Hyperresponse of PRL to TSH releasing hormone (TRH) was observed in five (three with hyperkinesia, one with tic and one with autism) of the thirteen patients before treatment and in seven (four with hyperkinesia, two with autism and one with tic) during treatment. Mean TSH response during treatment was not significantly different from that before treatment. However, three of the four autistic children showed hyperresponse of TSH to TRH before treatment, whereas only one also showed a hyperresponse during treatment. The pimozide treatment had no demonstrable influence on GH or cortisol secretion in response to insulin-induced hypoglycemia, or on serum T4 and T3 levels.

Effect of ACTH, adrenalectomy and the combination treatment on the density of 5-HT2 receptor binding sites in neocortex of rat forebrain and 5-HT2 receptor-mediated wet-dog shake behaviors.

The effect of ACTH and/or adrenalectomy on serotonin (5-HT)2 receptor binding sites was evaluated in the neocortex of rat forebrain. One day after the adrenalectomy or sham operation, ACTH (50 micrograms/day) was injected subcutaneously into adult male SD rats for 10 consecutive days. Saturation analysis showed that subchronic ACTH treatment significantly increased the Bmax values for 3H-ketanserin binding without any change in the Kd values. Moreover, this ACTH-induced increase in the Bmax values was prevented by adrenalectomy. The concentrations of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) measured by HPLC-ECD were not altered by these manipulations. Ten-day administration of corticosterone (20 and 50 mg/kg) also increased 5-HT2 receptor density in the neocortex of rat forebrain. 5-HT2 (and 5-HT1C) receptor agonist, (+/-)DOI-induced wet-dog shakes in ACTH and/or adrenalectomy-treated rats were also examined. Ten-day administration of ACTH enhanced (+/-)DOI-induced wet-dog shakes and this increase was prevented by adrenalectomy. These results indicate that subchronic adrenocorticotropin-adrenal axis activation of rats increases both the number of 5-HT2 receptors in neocortex of forebrain and the wet-dog shake responses induced by (+/-)DOI.

Serotonin but not norepinephrine-induced calcium mobilization of platelets is enhanced in affective disorders.

Intracellular calcium concentrations ([Ca++]i) in blood platelets from 11 depressed patients and 11 healthy controls were investigated. The resting [Ca++]i of platelets from depressed patients was 69.4 +/- 2.9 nM while that from controls was 74.6 +/- 4.0 nM. Serotonin (5-HT), at a concentration of 10 microM, increased [Ca++]i by 129.2 +/- 3.9 nM in platelets from depressed patients, which was significantly greater than that found in platelets from control subjects (105.2 +/- 6.0 nM). Norepinephrine (NE) 100 microM increased [Ca++]i by 46.1 +/- 7.1 nM in platelets from depressed patients, and by 38.6 +/- 6.1 nM in platelets from controls, respectively. These results indicate that 5-HT2 receptor function in platelets of depressed patients is enhanced, and support the hypothesis of hypersensitivity of 5-HT2 receptors in affective disorders.

A neurochemical study of a new mutant mouse presenting myoclonus-like involuntary movement: a possible model of spontaneous serotonergic hyperactivity.

The involuntary movements resembling the serotonin (5-HT) syndrome induced by 5-HT agonist, which is composed with symptoms such as head twitch, hind leg abduction and so on, are neurochemically evaluated in the new mutant mouse, Wriggle Mouse Sagami (WMS). Ritanserin (5-HT2 antagonist) and prazosin (alpha 1-adrenergic antagonist) both inhibited the symptoms, had a decrease in the number of times they fell down and prolonged the duration of sitting up, while SCH 23390 (dopamine1 antagonist) and YM-0911-2 (dopamine2 antagonist) did not affect them. Metergoline (5-HT1 and 5-HT2 antagonist) suppressed the locomotor activity, making it difficult to determine if it ameliorated the symptoms. The concentration of a metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) was higher than control values diffusely in the CNS except in the cerebral cortex. The accumulation of 5-HTP after the administration of amino acid decarboxylase inhibitor NSD 1015 was significantly enhanced in the hypothalamus, median raphe, cerebellum and pons. An increase in 5-HT and NA was also noted in the cerebellum. GABA was increased in the striatum. In the binding assay, the number of [3H]ketanserin binding sites was increased and that of [3H]prazosin binding sites was decreased in the striata. Meanwhile, no significant difference was observed either in the number of binding sites (Bmax) or the affinity (KD) in the [3H]5-HT binding study. The number of [3H]muscimol binding sites in the cerebellum was reduced with the dissociation constant (KD) unchanged. These results suggest the involvement of 'hyperserotonergic' neural systems, possibly due to the enhanced 5-HT synthesis, in the manifestation of the involuntary movements of WMS, with noradrenergic and GABAergic modification. WMS can be a useful model to study the function of the serotonergic system in the CNS.

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.

Effects of combined administration of imipramine and chlorpromazine on beta- and alpha 2-adrenergic receptors in rat cerebral cortex.

Administration of the combination of antidepressant and neuroleptic drugs has been reported to have a synergistic effect in the treatment of delusional depression. The effects of chronic coadministration of imipramine (IMIP) and chlorpromazine (CPZ) on beta-adrenergic and alpha 2-adrenergic binding sites in rat cerebral cortex were studied. The combination caused the same reduction in the number of beta-adrenergic receptors as IMIP alone. No changes in alpha 2-adrenergic receptors were observed with IMIP and/or CPZ.

Differential effect of subchronic dexamethasone treatment on serotonin-2 and beta-adrenergic receptors in the rat cerebral cortex and hippocampus.

The effect of the 10-day dexamethasone administration on serotonin-2 (5-HT2) and beta-adrenergic receptor binding sites was evaluated in rat cerebral cortex and hippocampus. The dexamethasone treatment (1, 2 and 5 mg/kg) significantly increased the density of the 5-HT2 receptor binding sites in a dose-dependent manner, whereas a decreased density of beta-adrenergic receptor binding sites was observed in rat cortex. In contrast, there were no significant differences in the densities of the 5-HT2 or beta-adrenergic receptor binding sites in rat hippocampus using dexamethasone. The results suggest that dexamethasone differentially modulates the 5-HT2 and beta-adrenergic receptor binding sites in rat brain.

Periodic maternal deprivation-induced potentiation of the negative feedback sensitivity to glucocorticoids to inhibit stress-induced adrenocortical response persists throughout the animal's life-span.

In this study, it was clearly demonstrated that the enhanced negative feedback sensitivity to glucocorticoids to inhibit stress-induced adrenocortical response, which was produced by periodic maternal deprivation (PMD) treatment for the first 3 weeks of life, did persist in rats tested at 66 and 92 weeks of life, suggesting that some stressful experience during early life permanently alters the adrenocortical response to stressful stimuli. This effect of PMD was not accompanied by an increased density of glucocorticoid receptor binding sites in the hippocampus from 93-week-old rats.

Regulation of synapse density by 5-HT2A receptor agonist and antagonist in the spinal cord of chicken embryo.

Identification of mechanisms that regulate the number of synapses in the brain has been a key issue for understanding the mechanism of plasticity. Here, we report that the density of synapses can be changed using an antagonist and/or an agonist of serotonin (5-HT) type 2A receptors in the chicken spinal cord. Because of the widespread distribution pattern of 5-HT fibers and 5-HT2A receptors in the central nervous system, 5-HT is thought to play a role in the formation and maintenance of synapses that are involved in normal brain function and mechanism of plasticity.

Direct activation of purified Go-type GTP binding protein by tricyclic antidepressants.

A growing body of evidence suggests that tricyclic antidepressant agents (TCAs) interact with GTP binding proteins (G proteins). We have investigated if TCAs directly alter the function of the purified Go protein which is specifically expressed in neuronal tissue. Several TCAs markedly enhanced the GTPase activity of Go protein in a pertussis toxin-susceptible manner, whereas MAO-inhibitor and anxiolytic agent did not. This enhancing effect of TCAs on Go function may be due to an increase in the GDP-GTP exchange reaction occurring on Go. Thus, it is very likely that TCAs can modify various signal transduction by directly interacting with G proteins in brain cells.

Serotonin-induced 5-HT1A receptor desensitization in C6BU-1 glioma cells transfected with 5-HT1A receptor gene.

In this study, it has been clearly demonstrated that a selective 5-hydroxytryptamine (5-HT)1A agonist, 8-OH-2-(di-n-propylamino)-tetraline (8-OH-DPAT, 1 microM) significantly inhibited forskolin (10 microM)-stimulated cyclic AMP (cAMP) accumulation in the C6BU-1 cells transfected with 5-HT1A receptor gene. Further, this 8-OH-DPAT-induced inhibition of forskolin-stimulated activity was significantly attenuated after pre-exposure to 5-HT (10 microM) for 12 h. Spiperone (10 microM), a 5-HT1A and 5-HT2A antagonist, prevented 5-HT-induced desensitization of 5-HT1A receptor, but a selective 5-HT2A receptor antagonist, ketanserin, did not. In addition, pre-exposure to a selective 5-HT2A agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 10 microM), for 24 h did not alter the inhibitory effect of 8-OH-DPAT on forskolin-stimulated cAMP accumulation in these transfected cells, suggesting that prolonged exposure to 5-HT induced 5-HT1A receptor desensitization, mediated by 5-HT1A receptor but not 5-HT2A receptors.

Effect of subchronic antidepressants administration on serotonin-stimulated phosphoinositide hydrolysis in para-chlorophenylalanine-treated rat hippocampal slices.

1. This study examines the effect of subchronic parachlorophenylalanine (PCPA) treatment upon serotonin (5-HT)-stimulated inositol monophosphate (IP-1) accumulation in rat hippocampal slices and also the effect of antidepressants upon this 5-HT response in the hippocampus from rats treated with or without concurrent administration of PCPA. 2. For high dose PCPA treatment, animals were injected intraperitoneally with 300 mg/kg daily for the first 5 days and then 100 mg/kg for 5 days, while for low dose PCPA treatment animals were injected for 10 days at a dose of 100 mg/kg. Imipramine or iprindole (15 mg/kg i.p.) was given once daily for 10 consecutive days. 3. 10-Day treatment with high dose of PCPA resulted in a significant increase in 5-HT-stimulated IP-1 accumulation, whereas low dose of PCPA had no significant effect upon the 5-HT response as compared to vehicle. 5-HT-stimulated IP-1 accumulation in rat hippocampus was not affected by subchronic treatment with imipramine or iprindole. The enhancement of the 5-HT response induced by high dose of PCPA was not attenuated by repeated antidepressants treatment.