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Neuronal Signaling Pathways: Genetic Insights Into the Pathophysiology Of ............................................................................................................................................................... HOT TOPICS 350 DISCLOSURE carry a (1;11)(q42.1; q14.3) translo- neuronal migration, axon guidance, In addition to income received from his primary cation; the chromosome 1 transloca- synapse formation, myelination, employer, Dr David Steffens has received honoraria for speaking at educational activities sponsored by tion break point falls between exon and oligodendrocyte development. Forest Pharmaceuticals and Wyeth Pharmaceuticals. 8 and 9 of DISC1, presumably result- NRG-1 activated Akt inhibits GSK3b, This work was partially supported by National Institute ing in loss of DISC1 expression. tying NRG1 signaling to Wnt and of Mental Health Grants P50 MH60451, R01 MH54846, and K24 MH70027. This finding has launched an entire DISC1 activity. The related effects ..................................................................... subfield of schizophrenia genetics and of DISC1 and NRG1 have been high- Alexopoulos GS, Meyers BS, Young RC, Campbell S, neurobiology, with an emphasis on lighted in a zebrafish model, in Silbersweig D, Charlson M (1997). ‘Vascular the role of the DISC1 gene product and which DISC1 loss produced develop- depression’ hypothesis. Arch Gen Psychiatry 54: 915–922. its protein interaction partners in mental deficits very similar to loss Pan CC, McQuoid DR, Taylor WD, Payne ME, Ashley- neurodevelopment and synaptic func- of NRG1 signaling, including failure of Koch A, Steffens DC (2009). Association analysis tion (Chubb et al, 2008). normal oligodendrocyte development of the COMT/MTHFR genes and geriatric depres- sion: An MRI study of the putamen. Int J Geriatr In the past year, DISC1 has been put and near total failure of olig2-positive Psychiatry 24: 847–855. into the context of key signal trans- cerebellar neuron development Qiu A, Taylor WD, Zhao Z, MacFall JR, Miller MI, Key duction pathways and other genetic (Wood et al, 2009). The effect of CR et al (2009). APOE related hippocampal shape alteration in geriatric depression. Neuroimage 44: findings. In one critical study psychotropic agents on these path- 620–626. (Mao et al, 2009), DISC1 was shown ways provides an additional link to Steffens DC, Taylor WD, McQuoid DR, Krishnan KR to modulate the ‘canonical’ Wnt- major mental illness. For instance, (2008). Short/long heterozygotes at 5HTTLPR and white matter lesions in geriatric depression. Int signaling pathway. This pathway lithium activates Akt and inhibits J Geriatr Psychiatry 23: 244–248. (Komiya and Habas, 2008) is activated GSK3b, whereas antipsychotic agents, Taylor WD, Zu¨ chner S, McQuoid DR, Payne ME, when a member of the Wnt family by antagonism of D2 receptors, MacFall JR, Steffens DC et al (2008). The brain- derived neurotrophic factor VAL66MET poly- of secreted glycoproteins binds a block the stimulatory effect of dopa- morphism and cerebral white matter hyperinten- member of the Frizzled receptor mine on Akt. sities in late-life depression. Am J Geriatr family along with coreceptors. Path- Overall, the convergence of genetic, Psychiatry 16: 263–271. Taylor WD, Steffens DC, Ashley-Koch A, Payne ME, way activation reduces GSK3b kinase pharmacological, and neurobiologi- MacFall JR, Potocky C et al (2009). Angiotensin activity, resulting in diminished phos- cal data have opened the door to receptor gene polymorphisms and 2-year phorylation of b-catenin. Unpho- multiple novel potential therapeutic change in cerebral hyperintense lesion volume in men. Mol Psychiatry, March 10 (E-pub ahead sphorylated b-catenin accumulates in targets in the DISC1–Wnt–NRG1 sys- of print). the cytoplasm and is translocated into tems, and this neurogenetic approach the nucleus, where it functions as a holds considerable promise for Neuropsychopharmacology Reviews (2010) 35, 349–350; doi:10.1038/npp.2009.135 transcriptional coactivator. Among future research. For instance, the other effects, this transcriptional recent association of the MHC locus activity can drive neuronal neurogen- on chromosome 6p with schizophre- esis. DISC1 directly interacts with nia (e.g., Stefansson et al, 2009) GSK3b, inhibiting GSK3b phosphor- supports the long standing concept ylation of b-catenin and thus increas- that environmental factors such as Neuronal signaling ing b-catenin-induced transcriptional infection may have a role in schizo- pathways: genetic activity. The effect is to mimic Wnt phrenia, and provides a rationale for insights into the pathway activation. Loss of DISC1 models of disease that encompass inhibits b-catenin-induced transcrip- both genetic and environmental fac- pathophysiology of tion, providing a potential mechanism tors. Associations of neurogranin on major mental illness by which DISC1 loss of function 11q24.2 and transcription factor 4 mutations might exert their effect. (TCF4) on 18q21.2 with schizophrenia Psychiatric genetics has turned a DISC1 has also been linked to (Stefansson et al, 2009) may lead to cornerFincreasingly robust findings pathways involving Neuregulin-1 new pathways with additional thera- can be placed in a neurobiological (NRG1), one of the most robust peutic targets. Psychiatric research has context, with practical implications candidate genes for schizophrenia entered an era in which genetic for understanding disease pathogen- (Mei and Xiong 2008). Extracellular findings implicate specific signaling esis and developing of therapeutics. NRG1, cleaved from Pro-NRG1, inter- pathways, leading to new insights into A milestone in this effort was the acts with and activates the ErbB family disease pathogenesis and the develop- discovery of the DISC1 (disrupted in of receptor protein kinases (ErbB2, 3, ment of new approaches to therapeutics. Schizophrenia 1) gene, found via 4, and EGFR), starting a cascade that 1,2,3 analysis of a large Scottish family Russell L Margolis and activates a number of partially over- 1,2,3,4 with a high rate of schizophrenia lapping pathways, including RafF Christopher A Ross 1Division of Neurobiology, Department of Psychiatry, and psychotic affective disorder. MEK–ERK and PI3K–Akt. NRG1 Johns Hopkins University School of Medicine, All affected members of the family signaling has been implicated in Baltimore, MD, USA; .............................................................................................................................................. Neuropsychopharmacology HOT TOPICS ............................................................................................................................................................... 351 2 Department of Neurology, Johns Hopkins University We reported (Boldrini et al, 2009) gration into brain circuits that regulate School of Medicine, Baltimore, MD, USA; 3Program in Cellular and Molecular Medicine, Johns that selective serotonin reuptake in- emotional responses to the environ- Hopkins University School of Medicine, Baltimore, hibitors and tricyclic antidepressants ment. MD, USA and increase dividing and neural progeni- In our study, the antidepressant- 4Departments of Pharmacology and Neuroscience, Johns Hopkins University School of Medicine, tor cells (NPCs) in the DG of depre- induced increase in NPCs and Baltimore, MD, USA ssed subjects (MDD), compared with dividing cells was associated with a E-mail: [email protected] untreated MDD patients or controls. larger volume of DG. Antidepressant In humans, antidepressants increase treatment is known to increase DISCLOSURE Potential conflicts of interest for RLM: Consultant the number of mitotic cells of all hippocampal volume in posttraumatic for AstraZeneca, grant support from Medivation, phenotypes in the DG, regardless of stress disorder (Bossini et al, 2007), Amarin, Pfizer, and Forest Pharmaceuticals. age. On the other hand, replication of but no similar data are available in No conflicts of interest for CAR. NPCs, as in lower mammals, decreases depression, although patients with ..................................................................... with age (Couillard-Despres et al, MDD have a smaller hippocampus. Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK (2008). The DISC locus 2009). This might explain why there The volume increase could be related in psychiatric illness. Mol Psychiatry 13: is a poor antidepressant response in to a restoration of cell number or 36–64. the elderly. neuropil, as antidepressants reverse Komiya Y, Habas R (2008). Wnt signal transduction pathways. Organogen 4: 68–75. The functional relevance of the dendritic shrinkage and improve cell Mao Y, Ge X, Frank CL, Madison JM, enhancement of neurogenesis by anti- survival, activating the antiapoptotic Koehler AN, Doud MK et al. (2009). Disrupted in depressants needs to be ascertained by protein Bcl-2 and brain-derived schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta- determining whether increased cell neurotrophic factor expression in catenin signaling. Cell 136: 1017–1031. proliferation is associated with im- mammals. Mei L, Xiong WC (2008). Neuregulin 1 in neural provement of symptoms in MDD. In Future studies must determine development, synaptic plasticity and schizophre- nia. Nat Rev Neurosci 9: 437–452. our study (Boldrini et al, 2009), a whether antidepressant response is Stefansson H, Ophoff RA, Steinberg S, Andreassen significant proportion of subjects died linked to increased neurogenesis, but OA, Cichon S, Rujescu D et al. (2009). Common by
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