Abstract
The membrane-bound axon guidance molecules netrin-G1 (NTNG1) and netrin-G2 (NTNG2) play a role in synaptic formation and maintenance. Non-coding single nucleotide polymorphisms (SNPs) in both genes have been reported to be associated with schizophrenia. The main aim of this study was to determine if NTNG1 and NTNG2 mRNA expression is altered in schizophrenia or bipolar disorder, and/or influenced by disease-associated SNPs. NTNG1 and NTNG2 mRNAs were examined in the medial and inferior temporal lobe using in situ hybridization and RT-PCR in the Stanley Medical Research Institute array collection, and in rat hippocampus during development and after antipsychotic administration. NTNG1 mRNA isoforms were also examined during human brain development. For NTNG1, the G1c isoform was reduced in bipolar disorder and with a similar trend in schizophrenia; expression of four other NTNG1 isoforms was unchanged. In both schizophrenia and bipolar disorder, NTNG2 mRNA was reduced in CA3, with reductions also found in CA4 and perirhinal cortex in bipolar disorder. The SNPs did not affect NTNG1 or NTNG2 mRNA expression. Both NTNG1 and NTNG2 mRNAs were developmentally regulated, and were unaltered by haloperidol, but NTNG2 mRNA was modestly increased by clozapine. These data implicate NTNG1 and NTNG2 in the pathophysiology of schizophrenia and bipolar disorder, but do not support the hypothesis that altered mRNA expression is the mechanism by which genetic variation of NTNG1 or NTNG2 may confer disease susceptibility.
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Acknowledgements
This study was supported by the UK Medical Research Council and the Stanley Medical Research Institute. We thank Jamie Anderson, Greg Bristow, and Mary Walker for technical assistance, and Dr Phil Burnet for provision of animal tissue. Post-mortem tissue was provided by the Stanley Medical Research Institute courtesy of Drs Michael B Knable, E Fuller Torrey, Maree J Webster, Serge Weis, and Robert H Yolken. This research would not have been possible without the participation of patients with schizophrenia and bipolar disorder, their families and control subjects and we are grateful for their generosity.
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Dr Eastwood: My research is funded by the UK Medical Research Council and NARSAD. I declare that, except for income received from my primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and that there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
Professor Harrison: My group's research is supported by the UK Medical Research Council, Stanley Medical Research Institute, NARSAD, Wellcome Trust, and an unrestricted educational grant from GlaxoSmithKline. In the past 3 years, I have received honoraria for giving educational lectures or chairing scientific meetings from Bristol Myers Squibb, GlaxoSmithKline, Janssen, Lilly, Merck, Sanofi, and Servier pharmaceutical companies, and I have been a scientific advisor to Curidium, Janssen, and Wyeth. There are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Eastwood, S., Harrison, P. Decreased mRNA Expression of Netrin-G1 and Netrin-G2 in the Temporal Lobe in Schizophrenia and Bipolar Disorder. Neuropsychopharmacol 33, 933–945 (2008). https://doi.org/10.1038/sj.npp.1301457
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DOI: https://doi.org/10.1038/sj.npp.1301457
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