General Summary

A Midei and J Licinio UCLA, Los Angeles, CA, USA

Molecular Psychiatry (2004) 9, 2–4. doi:10.1038/sj.mp.4001454

SCIENTIFIC CORRESPONDENCE phenotype has made the task of identifying susceptibility genes difficult. Fortunately, there are now signs Polymorphisms within 50 end of the Neuregulin 1 of real progress. Studies of genetic linkage and gene are genetically associated with schizophrenia in chromosomal abnormalities in schizophrenia have the Chinese population implicated a number of chromosomal regions. Re- JX Tang, WY Chen, G He, J Zhou, NF Gu, GY Feng, cently, evidence implicating individual genes within LHe some of the linked regions has been reported and more importantly replicated. These findings and their The 8p gene Neuregulin 1, which is one of the glial implications are reviewed. growth factors expressed during neurodevelopment and in the adult CNS, has recently been identified as a IMMEDIATE COMMUNICATION susceptibility gene for schizophrenia by linkage and LD mapping studies in the Icelandic and Scottish Association of estrogen receptor b gene polymorph- population. In the present work, the authors provide isms with bulimic disease in women independent statistical support for the previous ´ 0 M Nilsson, S Naessen, I Dahlman, AL Hirschberg, findings that schizophrenia is associated with the 5 J-A˚ Gustafsson, K Dahlman-Wright end of the Neuregulin 1 gene. The potential association between estrogen receptor b (ERb) and disease was explored in a group of bulimic HERV-W-related RNA detected in plasma from women. An association between two common poly- individuals with recent-onset schizophrenia or schi- morphisms in the ERb gene and disease was found zoaffective disorder in bulimic women compared to controls. More H Karlsson, J Schro¨der, S Bachmann, C Bottmer, detailed characterization of the ERb gene identified RH Yolken a novel variant changing the primary structure of the ERb protein in one bulimic patient. These findings The authors previously reported that certain patients, point towards a possible role of ERb and/or neighbor- suffering from recent-onset schizophrenia or schi- ing genes in the etiology of disease in bulimic zoaffective disorder, harbor differentially detectable patients. levels of endogenous retroviral RNA in CSF when compared to healthy control individuals. Presently, the authors report that, in plasma, retroviral RNA is Assessment of a prepulse inhibition deficit in a more prevalent among patients than healthy control mutant mouse lacking mGluR5 receptors individuals. Further studies aiming at identifying the SA Brody, SC Dulawa, F Conquet, MA Geyer role of retroviral transcripts in the etiopathogenesis of schizophrenia are warranted. Abnormalities in the glutamate system appear to contribute to symptoms of schizophrenia, including a filtering mechanism measured by a cross-species FEATURE REVIEW paradigm known as prepulse inhibition of startle (PPI). The authors examined the role of a specific The Molecular genetics of schizophrenia: new find- glutamate receptor, mGluR5, in PPI, using ings promise new insights mice lacking the mGluR5 gene. As observed in MJ Owen, NM Williams, MC O’Donovan persons with schizophrenia, PPI was disrupted dramatically in mice lacking mGluR5. These findings Individual differences in susceptibility to schizophre- support the glutamate hypothesis of schizophrenia nia are very largely genetic. However, the lack of a and identify a functional role for mGluR5 in sensor- simple one-to-one relationship between genotype and imotor gating. General Summary 3 ORIGINAL RESEARCH ARTICLES Intestinal permeability is decreased in anorexia nervosa Erythropoietin: a candidate compound for neuropro- P Monteleone, R Carratu`, M Cartenı´, M Generoso, tection in schizophrenia M Lamberti, L De Magistris, F Brambilla, B Colurcio, H Ehrenreich, D Degner, J Meller, M Brines, M Be´he´, M Secondulfo, M Maj M Hasselblatt, H Woldt, P Falkai, F Knerlich, S Jacob, N von Ahsen, W Maier, W Bru¨ck, E Ru¨ther, A Cerami, Malnourished and fasting individuals have increased W Becker, A-L Sire´n intestinal permeability (IP), suggesting an impaired barrier function of the intestinal mucosa. The authors Erythropoietin (EPO) is a candidate for neuroprotec- hypothesized that IP was enhanced in women with tion in brain disease. The purpose of this study was to anorexia nervosa, because of their chronic starvation prepare the ground for a first neuroprotective add-on and malnutrition. However, contrary to this hypoth- trial using EPO in schizophrenia to ameliorate esis, the authors found a decreased IP in underweight cognition and arrest degeneration. The authors de- anorexic women. This finding supports the occur- monstrate that: (1) intravenous EPO reaches the brain; rence of a potentiation of the barrier function of (2) EPO receptors are strongly expressed in brains of intestinal mucosa in malnourished anorexics, which schizophrenic patients; (3) EPO prevents nerve cell may protect these emaciated individuals from the death induced by antipsychotics; (4) EPO improves passage of potentially dangerous agents. cognition in mice. A genome-wide screen for genes influencing conduct disorder Modification of human 5-HT2C receptor function by DM Dick, T-K Li, HJ Edenberg, V Hesselbrock, Cys23Ser, an abundant, naturally occurring amino- J Kramer, S Kuperman, B Porjesz, K Bucholz, A Goate, acid substitution J Nurnberger Jr, T Foroud M Okada, JK Northup, N Ozaki, JT Russell, M Linnoila, D Goldman Genome-wide linkage analyses of retrospectively reported childhood conduct disorder and conduct A human serotonin 5-HT2C receptor gene polymorph- disorder symptomatology were performed in the ism leads to substitution of cysteine for serine at Collaborative Study on the Genetics of Alcoholism codon 23 (Cys23Ser). Cys23Ser has been reported to sample. The results suggest that regions on chromo- be associated with various mental disorders and drug somes 19 and 2 may contain genes conferring risk to response. Thus, in the present study, the authors conduct disorder. This study represents the first assessed whether Cys23Ser could affect receptor genome-wide screen directed toward identifying function. Results indicated that Ser23 may be con- genes contributing to childhood conduct disorder. stitutively more active and desensitized easier than Cys23. Ser23 appears to be an abundant candidate allele, which could directly influence interindividual Findings in an independent sample support an variation in behavior, susceptibility to mental dis- association between bipolar affective disorder and order, and drug response. the G72/G30 locus on chromosome 13q33 Y-S Chen, N Akula, SD Detera-Wadleigh, TG Schulze, J Thomas, JB Potash, JR DePaulo, MG McInnis, NJ Cox, FJ McMahon Interleukin-1a (IL-1a) induced activation of p38 mitogen-activated protein kinase inhibits glucocorti- Previous studies have implicated the genes G72 and coid receptor function G30, on chromosome 13q33, in both schizophrenia X Wang, H Wu, AH Miller and bipolar disorder. In this issue, Chen et al show that the reported association between bipolar disorder Previous studies have shown that the pro-inflamma- and markers near these genes can be reproduced in an tory cytokine interleukin (IL)-1 can disrupt glucocor- independent sample. The new findings involve ticoid receptor function, potentially contributing to different alleles than those reported previously, impaired feedback regulation of neuroendocrine and suggesting a complex relationship between disease immune responses in patients with neuropsychiatric and genetic variation at this locus. Further studies are and/or inflammatory disorders. This study demon- needed to identify variants that alter function and strates that IL-1 inhibits glucocorticoid receptor modify disease risk. function in mouse fibroblasts by activating p38 mitogen-activated protein kinase (MAPK) signal transduction pathways. The data suggest that the Possible evidence for a common-risk locus for p38 MAPK pathway may serve as a relevant ther- bipolar affective disorder and schizophrenia on apeutic target to reverse impaired glucocorticoid chromosome 4p16 in patients from the Faroe Islands receptor function in neuropsychiatric and/or inflam- TD Als, HA Dahl, TJ Flint, AG Wang, M Vang, O Mors, matory disorders. TA Kruse, H Ewald

Molecular Psychiatry General Summary 4 The present study supports the possibility that a locus aggressive threat behavior. The physiogenetic simi- on 4p16.1 may predispose to schizophrenia as well as larity between rhesus monkeys and humans supports bipolar affective disorder. In searching for a joint risk the use of nonhuman primates to investigate the locus in a genetic isolate, a number of overlapping physiological and behavioral relevance of human mu- segments were supported by increased sharing among opioid receptor polymorphisms. patients of one or more haplotypes. Chromosome 4p16 has also been implied in studies of patients collected from other neighboring and genetically Serotonin-2A receptor gene locus does not contain related populations. common polymorphism affecting mRNA levels in adult brain A mu-opioid receptor single nucleotide polymorph- NJ Bray, PR Buckland, H Hall, MJ Owen, ism in rhesus monkey: association with stress MC O’Donovan response and aggression GM Miller, J Bendor, S Tiefenbacher, H Yang, Relative expression of the 102T- and C-alleles of the MA Novak, BK Madras HTR2A gene was measured in 23 genomic hetero- zygotes using mRNA derived from cerebral cortex. No In humans, variations in the mu-opioid receptor gene difference was observed in the ratio of the two alleles are associated with differences in receptor affinity for compared with genomic DNA, indicating that they are b-endorphin and stress response. The authors dis- equally expressed. A further absence of variability in covered a single-nucleotide polymorphism in the allelic ratios between mRNA samples suggests that rhesus monkey mu-opioid receptor-coding region the HTR2A locus is unlikely to contain additional (C77G) that is associated with increased affinity for common polymorphisms or epigenetic modification b-endorphin, decreased cortisol levels, and increased that alter HTR2A mRNA levels in adult brain.

Molecular Psychiatry