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Synaptic Modulators Nrxn1 and Nrxn3 Are Disregulated in a Disc1 Mouse

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Synaptic Modulators Nrxn1 and Nrxn3 Are Disregulated in a Disc1 Mouse Letters to the Editor 585 National University of Ireland Galway, Galway, Ireland; 4Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA; 5Center for Integrated Molecular Brain Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark and 6Department of Psychiatry, Laureate Institute for Brain Research, University of Oklahoma College of Medicine, Tulsa, OK, USA E-mail: [email protected] 7These senior authors contributed equally to this paper. References 1 Ichimiya T, Suhara T, Sudo Y, Okubo Y, Nakayama K, Nankai M et al. Biological Psychiatry 2002; 51: 715–722. 2 Cannon DM, Ichise M, Rollis D, Klaver JM, Gandhi SK, Charney DS et al. Biol Psychiatry 2007; 15: 870–877. 3 Cannon DM, Ichise M, Fromm SJ, Nugent AC, Rollis D, Gandhi SK et al. Biol Psychiatry 2006; 60: 207–217. 4 Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. American Journal of Human Genetics 2007; 81: 559–575. Figure 1 Map of t-values from voxel-wise analysis of 5 Shioe K, Ichimiya T, Suhara T, Takano A, Sudo Y, Yasuno F et al. Synapse 2003; 48: 184–188. rs6741892, overlaid on a sample axial magnetic resonance 6 Kalbitzer J, Frokjaer VG, Erritzoe D, Svarer C, Cumming P, imaging slice at the level of the medial thalamus (z = 6 mm). Nielsen FA et al. Neuroimage 2009; 45: 280–285. Bilaterally, T-allele carriers (n = 13) have greater serotonin- 7 Erritzoe D, Holst K, Frokjaer VG, Licht CL, Kalbitzer J, Nielsen FA transporter-binding potential than AA homozygotes (n = 42). et al. J Neurosci 2010; 30: 3391–3397. The color bar indicates the range of t-values displayed (max 8 Frey PA. FASEB J 1996; 10: 461–470. t = 6.56, df = 53, P = 2.3 Â 10À8). 9 Blakely RD, Ramamoorthy S, Schroeter S, Qian Y, Apparsundaram S, Galli A et al. Biol Psychiatry 1998; 44: 169–178. 10 Blakely RD, De Felice LJ, Hartzell HC. J Exp Biol 1994; 196: 263–281. may also have a role in N-glycosylation, which is important for surface expression of 5-HTT.10 To our knowledge, this is the first GWAS of brain 5-HTT. These preliminary results suggest that neuro- Synaptic modulators Nrxn1 imaging phenotypes could represent informative targets for a GWAS, even in relatively small samples. and Nrxn3 are disregulated Further studies are needed to confirm these in a Disc1 mouse model of findings and determine the underlying biological mechanisms. schizophrenia Conflict of interest Molecular Psychiatry (2011) 16, 585–587; doi:10.1038/ The authors declare no conflict of interest. mp.2010.134; published online 15 February 2011 Acknowledgments DISC1 is a leading candidate gene for schizophrenia This research is funded by the NIMH Intramural and related disorders. It has several modes of action Research Program. through protein–protein interaction at multiple cel- lular locations, including the synapse.1,2 Previously, X Liu1, DM Cannon2,3, N Akula1, PR Moya4, we developed and characterised a mouse line carry- GM Knudsen5, TE Arentzen5, J Steele1, G Laje1, ing an ENU-induced Disc1 missense mutation, L100P. WC Drevets2,6,7 and FJ McMahon1,7 The mice exhibit behavioural, anatomical and phar- 1Genetics of Mood and Anxiety Disorders Section, macological phenotypes related to schizophrenia; National Institute of Mental Health, National schizophrenia-like endophenotypes, including Institutes of Health, Bethesda, MD, USA; 2Section on deficits in pre-pulse inhibition, latent inhibition Neuroimaging in Mood and Anxiety Disorders, and working memory, and, at the molecular level, National Institute of Mental Health, National reduced DISC1–PDE4B interaction.3 Here, we show Institutes of Health, Bethesda, MD, USA; 3Department that the L100P mutation disregulates expression of Psychiatry, Clinical Neuroimaging Laboratory, of the synaptic modulators Nrxn1 and Nrxn3 at Molecular Psychiatry Letters to the Editor 586 Figure 1 Expression analysis using Taqman qRT-PCR. (a), fold change and P-values (Mann–Whitney’s U-test) for Nrxn1 and Nrxn3 from the Illumina array, qRT-PCR on array RNA and qRT-PCR on an independent sample set. (b and c), Developmental expression profiles for Nrxn1 and Nrxn3 from E13 through adulthood (12 weeks). RNA from E13–E18 from whole brain, RNA from P1–adult from hippocampal tissue. key points during development, as well as in the observed at E15, E18, P7 and adult, with the largest adult mouse. Nrxn1 is involved in maintenance of differences being increased expression in the L100P synaptic junctions and is a mediator of intracellular mutant at E15 and P7, and decreased expression at E18 signalling, modulating maturation and differentiation (Figures 1b and c). of synapses.4 Nrxn3 is a membrane protein involved It is noteworthy that the L100P Nrxn1 and Nrxn3 in cell adhesion, synaptic transmission and neuro- expression profiles differ most from the wildtype transmitter secretion.4 between E18, a stage of synaptic formation and Both the Neurexin gene family and DISC1 have neuronal maturation, and P7, when neurite out- been independently implicated in schizophrenia and growth, myelination, synaptic pruning and apoptosis autism. A missense mutation and copy number occur.9 Disregulation of such key processes may lead variants in NRXN1 were first linked to autism (ref. 5 to alterations in brain development and function. and references within), and copy number variants in Kitamura et al.10 showed that both Nrxn1 and Nrxn3 this gene were subsequently reported to be more are synaptic activity-dependent genes; they are down- abundant in schizophrenia than in controls (ref. 6 and regulated in the presence of the potent neurotoxin references within). Recent pathway analysis of the tetrodotoxin and somewhat upregulated by it’s genes identified by three large genome-wide associa- withdrawal. Taking note of the emerging evidence tion studies of bipolar disorder and schizophrenia for a synaptic function for Disc1,2 we hypothesise (ISC, GAIN and WTCCC) suggested that perturbation that in the developing embryo, the presence of of cell adhesion molecules may be central to devel- mutant Disc1 at the synapse affects synaptic function, opment of neuropsychiatric illness and, furthermore, leading to a change in synaptic activity-mediated identified NRXN1 as being one of two genes asso- transcription of Nrxn1, Nrxn3 and other genes. ciated in all three studies.7 TheroleofDISC1 in We speculate that this change in transcription of schizophrenia and bipolar disorder is well established,1 Nrxn1 and 3 (and possibly other synaptic genes) but a number of recent studies of autism spectrum results in altered formation and function of inhibitory disorders have found association between DISC1 and excitatory synapses during this critical develop- variants and these conditions also (ref. 8 and references mental period. within). To summarise, here we demonstrate, for the first We used Illumina (Illumina, Essex, UK) whole- time, that there is a DISC1-dependant mechanism genome expression profiling of 47 000 mouse brain for regulating neurexin gene expression. The striking transcripts to compare hippocampal samples from the disregulation of Nrxn1 expression in the L100P Disc1 Disc1 L100P mutant line (n = 12) and wild-type control mutant animals provides a first functional link mice (n = 12) at 12 weeks of age. Expression of both between these two prominent genetic candidates for Nrxn1 and Nrxn3 showed a modest, but significant risk of schizophrenia and of autism. upregulation in the L100P mutant mice compared with wild-type controls (Figure 1a). This was confirmed by quantitative RT-PCR analysis of both the original Conflict of interest array RNA and an independent sample set (Figure 1a). This prompted us to examine Nrxn1 and Nrxn3 The authors declare no conflict of interest. expression profiles across development in the L100P mutant. Expression profiles of both genes in the mutant SM Brown1, SJ Clapcote2, JK Millar1, HS Torrance1, animals differed strikingly from those observed in wild- SM Anderson1, R Walker1, A Rampino1, JC Roder3, type mice. Significant differences in expression were PA Thomson1,4, DJ Porteous1,4 and KL Evans1,4 Molecular Psychiatry Letters to the Editor 587 1Psychiatric Genetics, Medical Genetics Section, system, has been implicated in the etiology of BD, Centre for Molecular Medicine and Institute of genetic association findings have been inconsistent.2 Genetics and Molecular Medicine, Molecular One of the most strongly associated polymorphisms Medicine Centre, Western General Hospital, in the recent Wellcome Trust Case Control Consor- University of Edinburgh, Edinburgh, UK; tium genome-wide association study of BD (1868 2Centre for Cognitive Ageing and Cognitive cases, 2938 controls)3 is located in the GABRB1 gene, Epidemiology, Medical Genetics Section, Molecular which encodes the GABAA receptor b1 subunit. The Medicine Centre, Western General consortium conducted a further analysis to reduce Hospital, University of Edinburgh, Edinburgh, UK; biological heterogeneity. In this second analysis, the 3Samuel Lunenfeld Research Institute, strongest signal at this polymorphism was found in Mount Sinai Hospital, Joseph and Wolf Lebovic the subsample meeting Research Diagnostic Criteria4 Health Complex, 600 University Ave., for schizoaffective, bipolar type (SABP) (n = 279). Toronto, ON, Canada and 4Institute of Membrane and Association signals were also found in the SABP Systems Biology, University of Leeds, Leeds, UK subsample at GABRA4, GABRB3, GABRA5, and E-mail: [email protected] GABRR3 (experiment-wide P = 6.6 Â 10À5). This pro- vided strong, independent evidence in support of References the hypothesis that variation in other GABAA receptor genes is associated with risk for the SABP phenotype. 1 Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. No association was found with schizophrenia. Mol Psychiatry 2008; 13: 36–64. We aimed to replicate these findings in our German 2 Hayashi-Takagi A, Takaki M, Graziane N, Seshadri S, Murdoch H, Dunlop AJ. et al. Nat Neurosci 2010; 13: 327–332. samples using the set-based approach.
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