General Summary F Sissingh, I Alvarado and J Licinio

UCLA, Los Angeles, CA, USA

Molecular Psychiatry (2002) 7, 1033–1035. doi:10. cessing. The review also presages promising 1038/sj.mp.4001261 approaches using mouse models to extend this work.

SCIENTIFIC CORRESPONDENCE IMMEDIATE COMMUNICATION − Association of WKL1 with catatonic schizophrenia 5-HT2A promoter polymorphism 1438G/A in PAJ Leegwater, PKI Boor, JC Pronk, MS van der children and adolescents with obsessive-compulsive Knaap disorders S Walitza, C Wewetzer, A Warnke, M Gerlach, The authors have found 26 mutations in MLC1 (WKL1), F Geller, G Gerber, T Go¨ rg, B Herpertz Dahlmann, which segregated with the recessive phenotype of E Schulz, H Remschmidt, J Hebebrand, A Hinney Megalencephalic Leukoencephalopathy with Subcort- − ical Cysts in 24 families. They never observed any form An analysis of the promoter polymorphism 1438G/A of schizophrenia in the patients or in the family mem- of the 5-HT2A-receptor gene in 55 children and ado- bers who carry the mutations. The authors suggest that lescents with obsessive compulsive disorder (OCD) the missense mutation found by Lesch and coworkers and in 223 controls exhibited a positive association in the same gene is probably not involved in the domi- between OCD and the A-allele. Both genotype and nant phenotype of catatonic schizophrenia. allele frequencies differed significantly between the groups. This is the first association study based on children and adolescents with OCD pertaining to this poly- Reply concerning KIAA0027 (WKL1, MLC1) and morphism. psychosis: white matters J Meyer, SJ Scherer, R Mo¨ ssner, KP Lesch ORIGINAL RESEARCH ARTICLES KIAA0027, which may be involved in catatonic schizo- Serotonin transporter gene polymorphism, phrenia (SCZD10, MIM 605419), is also likely to play a differential early rearing, and behavior in rhesus critical role in myelination and in diseases of the white monkey neonates matter, such as megalencephalic leukoencephalopathy M Champoux, A Bennett, C Shannon, JD Higley, with subcortical cysts (MLC, MIM 604004). The poten- KP Lesch, SJ Suomi tial function of KIA0027 in myelination is interesting in the light of the increasingly appreciated hypothesis The authors conducted a retrospective association that some forms of schizophrenia-like psychosis rep- study on rhesus macaque infants homozygous for the resent leukoencephalopathies or myelinopathies and long variant of the serotonin transporter gene regulat- that a variety of neurodegenerative disorders with a ory region or heterozygous for the short and long form. genetic, vascular, or inflammatory etiology that lead to Thirty-six mother-reared, and 79 nursery-reared monk- white matter dysfunction and disrupted cortical-stria- eys were assessed during month 1 postnatal on a stan- tal-limbic connectivity can be associated with psy- dardized primate infant neurobehavioral examination. chotic episodes. Heterozygotes demonstrated more affective responding than homozygotes. Nursery-reared, but not mother- reared, l/s infants exhibited lower orientation scores REVIEW than l/l infants. Mouse genetic models for prepulse inhibition: an early review Tau negative frontal lobe dementia at 17q21: MA Geyer, KL McIlwain, R Paylor significant finemapping of the candidate region to a 4.8 cm interval The authors critically evaluate studies using murine R Rademakers, M Cruts, B Dermaut, K Sleegers, genetic models to investigate prepulse inhibition of SM Rosso, M Van den Broeck, H Backhovens, J van startle, a measure of sensorimotor-gating deficits in Swieten, CM van Duijn, C Van Broeckhoven schizophrenia. Building on extensive human and rat studies of prepulse inhibition, work with genetically The authors report the results of a genome-wide search engineered mice has generated new insights into the in a four-generation pedigree with frontotemporal genetics, neurobiology, and psychopharmacology of dementia characterized by dense ubiquitin-positive this robust cross-species form of information pro- tau-negative neuronal inclusions. They identified a General Summary 1034 candidate region of 4.8 cM between D17S1787 and Identification of a novel variant of the human NR2B D17S958, containing MAPT, with a maximum multi- gene promoter region and its possible association point LOD score of 5.51 at marker D17S951. Despite with schizophrenia extensive mutation analysis, no MAPT mutations were R Miyatake, A Furukawa, H Suwaki detected. The authors suggest that the apparent In this study, the authors determined the nucleotide absence of MAPT mutations combined with the lack of sequence of the 5Ј-upstream region of the human tau pathology is highly suggestive for another defective NMDA receptor 2B (NR2B) subunit gene and identified gene at 17q21 responsible for FTD in this family. a novel T-200G variant that appears to be significantly associated with schizophrenia. This variant has a marked effect on the NGF-induced expression of the Dopamine D2S and D2L receptors may differentially NMDA2B gene. These findings suggest that this variant contribute to the actions of antipsychotic and may be involved in glutamate dysfunction associated psychotic agents in mice with the development of schizophrenia. R Xu, D Hranilovic, LA Fetsko, M Bucan, Y Wang

The authors investigated the role of dopamine D2L and The plasma levels of interleukin-12 in D2S receptors in the mechanisms of action of clinically schizophrenia, major depression, and bipolar mania: used dopaminergic drugs, using D2L knockout mice as effects of psychotropic drugs a model. They found that D2L may play a prominent YK Kim, IB Suh, H Kim, CS Han, CS Lim, SH Choi, role in the motor side effects induced by typical anti- J Licinio psychotics, whereas D2S may have a greater impact on the therapeutic actions of atypical antipsychotics. Interleukin-12 (IL-12) is a pro-inflammatory cytokine These findings may provide novel insights for that is produced primarily by monocyte and macro- developing better antipsychotics. phage and plays a central role in promoting type I T helper cell-specific cellular immunity. The authors found that the IL-12 levels of major depression victims were significantly increased, with no difference in the Decreased muscarinic receptors in the dorsolateral occurrence of schizophrenia or bipolar mania. More- prefrontal cortex of subjects with schizophrenia over, IL-12 levels of the three patients groups were B Dean, M McLeod, D Keriakous, J McKenzie, E Scarr decreased significantly after 8 weeks of treatment. The In this paper, the authors show that there is a decrease authors suggest that the activation of an inflammatory in muscarinic receptors but not muscarinic receptors in response system, especially Th-1 like cells, would be the prefrontal cortex from subjects with schizophrenia. related to the pathophysiology of major depression and This change was not present in another region of the repeated administration of antidepressant or antipsy- cortex, not thought to be involved in the pathology of chotics would suppress IL-12 plasma levels in psychi- the disorder. These data argue that changes in the chol- atric patients. inergic system of the brain are involved in the pathology of schizophrenia. Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive Mutation screening and LD mapping in the VCFS disorders deleted region of chromosome 22q11 in YWY Yu, SJ Tsai, TJ Chen, CH Lin, CJ Hong schizophrenia using a novel DNA pooling approach NM Williams, G Spurlock, N Norton, HJ Williams, The authors investigated inter-individual variations in ML Hamshere, M Krawczak, G Kirov, I Nikolov, response to SSRI treatment in a Chinese population L Georgieva, S Jones, AG Cardno, MC O’Donovan, and got a result in accordance with the other three MJ Owen studies performed on the western countries. They demonstrated an association between a better response to The authors examined whether variation within six SSRI antidepressant and the ‘long’ allele of 5-HTTLPR, genes from the VCFS critical region at 22q11 (DGSC, and accordingly refuted the argument that the associ- Stk22A1, DGSI, Gscl, Slc25A1 and Znf74) confers sus- ation would vary with ethnic background. ceptibility to schizophrenia. Pooled genotyping revealed no significant differences in the allele fre- Combined action of the ACE D and the G-protein ␤3 quencies for any polymorphism between cases and T allele in major depression: a possible link to controls. In addition, they also attempted to define the cardiovascular disease? location of a schizophrenia susceptibility locus by per- B Bondy, TC Baghai, P Zill, R Bottlender, M Jaeger, forming association mapping using seven microsatel- C Minov, C Schu¨ le, P Zwanzger, R Rupprecht, lites spanning the VCFS region. Marker D22S944 pro- RR Engel vided evidence for association in a sample of 368 cases and 368 controls and transmission disequilibrium in a Although it is well established that depression is a further sample of 278 parent–proband trios. major risk factor for the development of cardiovascular

Molecular Psychiatry General Summary 1035 disease and that cerebrovascular disease may contrib- Tryptophan hydroxylase immunoreactivity is altered ute to the development of depression, the underlaying by the genetic variation in postmortem brain pathophysiological mechanisms are not elucidated. As samples of both suicide victims and controls both disorders have a considerable genetically influ- H Ono, O Shirakawa, N Kitamura, T Hashimoto, enced susceptibility, genes or gene–gene interactions N Nishiguchi, A Nishimura, H Nushida, Y Ueno, might be important for unravelling pathogenetic mech- K Maeda anisms of these multifactorial diseases. The authors Serotonergic dysfunction is thought to be involved in investigated the angiotensin I converting enzyme the biological pathogenesis of suicide. In this study, (ACE) ID and the G-protein ␤3-subunit (G␤3) C825T both tryptophan hydroxylase (TPH) immunoreactivity polymorphisms in 201 patients with unipolar major and serotonin receptor 2A (5HT2A) receptor density depression and 161 controls. Both gene variants have were measured in the prefrontal cortex of postmortem earlier been associated with either cardiovascular dis- brains and no significant differences were found in ease or affective disorders, making them good candi- these serotonergic markers between suicide victims dates for a combined investigation. Their analysis and controls. This article also provides the first evi- show that the same allelic combination of the two dence that the AA genotype of the A218C polymor- genes that was earlier associated with myocardial phism of the TPH gene showed higher TPH immuno- infarction (ACE ID/DD—G␤3 TT genotype) also reactivity along with lower 5HT2A receptor density increases vulnerability for depressive disorder and than did any other genotypes. might thus be one link for the interaction between both disorders. J Licinio, MD Editor

Molecular Psychiatry