PM495. Neuropathology and functional analysis of schizophrenia associated variant in the MIR137 locus

So-called D-neuron (trace amine (TA) neuron) is the ligand neuron of trace amine-associated receptor, type 1 (TAAR1). Reduced stimulation of TAAR1 on dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) has been revealed to increase firing frequency of VTA DA neurons. A Patent Cooperation Treaty (PCT)-required histochemical methods (K. Ikemoto) were used to specify subgroups of D-neurons in the human brain (Ikemoto et al. 1997, 2016 (in press)), and to show D-neuron decrease in the nucleus accumbens (Acc) (D16, subgroup of D-neurons) of postmortem brains with schizophrenia (Ikemoto et al. 2003). The human D-neuron system is found to be far developed in the forebrain in comparison with that of other species, including non-human primates (Kitahama et al.2009). TA decrease caused by D-neuron reduction, and consequent TAAR1 stimulation decrease on terminals of midbrain VTA DA neurons leads to mesolimbic DA hyperactivity. Neural stem cell (NSC) dysfunction in the subventricular zone of lateral ventricle, which overlaps with the Acc, is supposed to be the cause of D-neuron reduction of schizophrenia. The rational is that the “D-cell hypothesis (TA hypothesis)” (Ikemoto 2012) is essential hypothesis to link DA hypothesis (Hokfelt et al, 1974) with NSC dysfunction hypothesis (Reif et al. 2006). From a therapeutic direction, (1) TAAR1 agonists or TAAR1 partial agonists (Revel et al. 2013), (2) DA D2 antagonists, and (3) neurotropic substances (e.g., brainderived neurotrophic factor (BDNF), lithium, anticonvulsants, and antidepressants) have potential to normalize mesolimbic DA hyperactivity. Intranasal administration of these neuroactive substances and/or their precursors to reach the neuroleptic acting site, such as the subventricular-accumbal region, by using nanotechnology, is a possible prospective therapeutic strategy, which is devoid of gastrointestinal side effects. PM495 Neuropathology and functional analysis of schizophrenia associated variant in the MIR137 locus Murray Cairns, Heath Cairns, Adam Carroll, Simonne Sherwin University of Newcastle, Australia Abstract Small non-coding microRNA (miRNA) coordinate mRNA translation in the brain, and their dysregulation has significant consequences in neurodevelopmental disorders. This hypothesis is supported by strong genetic evidence at the genome-wide associated variant in MIR137 (rs1625579) in recent PGC mega analysis of schizophrenia. We used a TaqMan genotyping and expression strategy to investigate the allelic expression (rs2660304) in postmortem DLPFC from subjects with schizophrenia and controls with no history of psychiatric disorder (n=74). While no significant difference was observed in the expression of miR-137 in postmortem DLPFC between the controls and schizophrenia, we found that mature miR-137 expression was significantly reduced in the samples homozygous for the risk allele compared to those homozygous for the alternative. Expression in the heterozygotes was not significantly different to either of the homozygotes, however, when we examined the allelic imbalance by differentiating pri-miR-137 expression at each allele (rs2660304), the risk allele was significantly lower compared to the alternative. Functional consequences of dysregulated miR137 in neurons was then examined human SH-SY5Y neuroblastsSmall non-coding microRNA (miRNA) coordinate mRNA translation in the brain, and their dysregulation has significant consequences in neurodevelopmental disorders. This hypothesis is supported by strong genetic evidence at the genome-wide associated variant in MIR137 (rs1625579) in recent PGC mega analysis of schizophrenia. We used a TaqMan genotyping and expression strategy to investigate the allelic expression (rs2660304) in postmortem DLPFC from subjects with schizophrenia and controls with no history of psychiatric disorder (n=74). While no significant difference was observed in the expression of miR-137 in postmortem DLPFC between the controls and schizophrenia, we found that mature miR-137 expression was significantly reduced in the samples homozygous for the risk allele compared to those homozygous for the alternative. Expression in the heterozygotes was not significantly different to either of the homozygotes, however, when we examined the allelic imbalance by differentiating pri-miR-137 expression at each allele (rs2660304), the risk allele was significantly lower compared to the alternative. Functional consequences of dysregulated miR137 in neurons was then examined human SH-SY5Y neuroblasts electroporated synthetic miR-137 and its antisense antagonist using gene expression profiling. While over expression of miR137 produced relatively few changes in target gene expression the repression of miR-137 in these cells produced changes in a large number of target genes, many of which have also been associated with schizophrenia. These genes were also enriched in several pathways believed to be involved in the neuropathology of the disorder including, axon guidance, glucocorticoid receptor signalling, ErbB signalling, dopamine-DARPP32 feedback in cAMP signalling, and mTOR signalling. This suggests that the risk variant in MIR137 is an eQTL and results in haploinsuficiency in carriers causing dysfunction in several pathways relevant to schizophrenia. PM496 How delusion is formed? Hee Jun Kim, M.Da, Jong Suk Park a,d, Ung Gu Kang a,b,c,* a Department of Psychiatry, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110–744, Republic of Korea b Department of Psychiatry and Behavioral Science, Seoul National