Selected rapporteur summaries from the XX World Congress of Psychiatric Genetics, Hamburg, Germany, October 14-18, 2012.

The XXth World Congress of Psychiatric Genetics (WCPG), sponsored by The International Society of Psychiatric Genetics (ISPG) took place in Hamburg, Germany on October 14-18, 2012. Approximately 600 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned sessions as rapporteurs. This manuscript represents topics covered in most, but not all, oral presentations during the conference, and some of the major notable new findings reported at this 2012 WCPG.

Role of chiral-induced spin selectivity in the radical pair mechanism of avian magnetoreception.

In this paper, we investigate the effect of chiral-induced spin selectivity (CISS) on the radical pair mechanism of avian magnetoreception. We examine the impact of spin selectivity on the avian compass sensitivity. In this analysis, we also consider the dipolar and exchange interactions and observe their interplay with CISS. We find that CISS results in a multifold increase in avian compass sensitivity. Interestingly, we also observe that CISS can counter the deleterious effect of dipolar interaction and increase system sensitivity. The analysis has been performed for the toy model (only one nucleus) and a more general case where we consider up to six nuclei from the cryptochrome radical pair system. We observe that the CISS allows the radical pair model to have more realistic recombination rates with good sensitivity. We also do an analysis of the functional window of the avian compass reported in behavioral experiments in the functional window. We could not find a parameter set where a functional window can be observed along with CISS. We also show the effect of spin relaxation on the system and show that under relaxation, CISS shows increased compass sensitivity compared to no CISS case.

Assessing oxidative pathway genes as risk factors for bipolar disorder.

OBJECTIVES: There is a growing body of evidence implicating oxidative stress and the glutathione system in the pathogenesis of major psychiatric illnesses, including schizophrenia and bipolar disorder. Here we investigate whether genes involved in oxidative stress regulation are associated with increased risk for bipolar disorder. METHODS: Four candidate genes were selected a priori from two different steps in the oxidative stress pathway, specifically the synthesis of glutathione [catalytic subunit of glutamate cysteine ligase (GCLC) and regulatory subunit of glutamate cysteine ligase (GCLM)] and the removal of reactive oxygen species [superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3)]. Haplotype tagging and functional nucleotide polymorphisms were selected in each gene and tested for association with bipolar disorder under narrow (n = 240) and broad (n = 325) phenotypic models, compared to healthy controls (n = 392, comprising 166 psychiatrically assessed unaffected controls plus 226 healthy individuals). RESULTS: Single marker association analysis did not reveal significant association with bipolar disorder; however, haplotypes in the SOD2 gene showed nominal association (global chi(2) = 8.94, p = 0.03; broad model). Interaction analysis revealed a significant interaction between SOD2 and GPX3 haplotypes, which further increases risk for bipolar disorder (odds ratio = 2.247, chi(2) = 9.526, p = 0.002, corrected p = 0.029). CONCLUSIONS: Further characterization of the SOD2 and GPX3 interaction using larger cohorts is required to determine the role of these oxidative pathway genes as risk factors for bipolar disorder.

Magnetic resonance imaging of blood-brain barrier permeability in ischemic stroke using diffusion-weighted arterial spin labeling in rats.

Diffusion-weighted arterial spin labeling magnetic resonance imaging has recently been proposed to quantify the rate of water exchange (Kw) across the blood-brain barrier in humans. This study aimed to evaluate the blood-brain barrier disruption in transient (60 min) ischemic stroke using Kw magnetic resonance imaging with cross-validation by dynamic contrast-enhanced magnetic resonance imaging and Evans blue histology in the same rats. The major findings were: (i) at 90 min after stroke (30 min after reperfusion), group Kw magnetic resonance imaging data showed no significant blood-brain barrier permeability changes, although a few animals showed slightly abnormal Kw. Dynamic contrast-enhanced magnetic resonance imaging confirmed this finding in the same animals. (ii) At two days after stroke, Kw magnetic resonance imaging revealed significant blood-brain barrier disruption. Regions with abnormal Kw showed substantial overlap with regions of hyperintense T2 (vasogenic edema) and hyperperfusion. Dynamic contrast-enhanced magnetic resonance imaging and Evans blue histology confirmed these findings in the same animals. The Kw values in the normal contralesional hemisphere and the ipsilesional ischemic core two days after stroke were: 363 ± 17 and 261 ± 18 min-1, respectively (P < 0.05, n = 9). Kw magnetic resonance imaging is sensitive to blood-brain barrier permeability changes in stroke, consistent with dynamic contrast-enhanced magnetic resonance imaging and Evans blue extravasation. Kw magnetic resonance imaging offers advantages over existing techniques because contrast agent is not needed and repeated measurements can be made for longitudinal monitoring or averaging.

Methylene blue and normobaric hyperoxia combination therapy in experimental ischemic stroke.

INTRODUCTION: Ischemic stroke is a global burden that contributes to the disability and mortality of millions of patients. This study aimed to evaluate the efficacy of combined MB (methylene blue) and NBO (normobaric hyperoxia) therapy in experimental ischemic stroke. METHODS: Rats with transient (60 min) MCAO (middle cerebral artery occlusion) were treated with: (1) air + vehicle (N = 8), (2) air + MB (N = 8), (3) NBO + vehicle (N = 7), and (4) NBO + MB (N = 9). MB (1 mg/kg) was administered at 30 min, again on days 2, 7, and 14 after stroke. NBO was given during MRI (30-150 min) on day 0, and again 1 h each during MRI on subsequent days. Serial diffusion, perfusion and T2 MRI were performed to evaluate lesion volumes. Foot-fault and cylinder tests were performed to evaluate sensorimotor function. RESULTS: The major findings were: (1) NBO + MB therapy showed a greater decrease in infarct volume compared to NBO alone, but similar infarct volume compared to MB alone, (2) NBO + MB therapy accelerated sensorimotor functional recovery compared to NBO or MB alone, (3) Infarct volumes on day 2 did not change significantly from those on day 28 for all four groups, but behavioral function continued to show improved recovery in the NBO + MB group. CONCLUSIONS: These findings support the hypothesis that combined NBO + MB further improves functional outcome and reduces infarct volume compared to either treatment alone and these improvements extended up to 28 days.

Effects of stroke severity and treatment duration in normobaric hyperoxia treatment of ischemic stroke.

In order to improve clinical trial design and translation of normobaric oxygen (NBO) treatment of ischemic stroke, NBO treatment parameters need to be better understood. This study investigated NBO treatment efficacy at two different stroke severities and two NBO treatment durations in rats. For the 60-min middle cerebral artery occlusion (MCAO), NBO treatment for 25 min and 150 min were studied. For the 90-min MCAO, NBO treatment for 55 min and 150 min were studied. Cerebral blood flow (CBF), apparent diffusion coefficients (ADC) and T2 MRI were acquired during occlusion prior to treatment, after reperfusion, and 48h after MCAO. The effects of NBO treatment on lesion volumes, and CBF, ADC and T2 of ischemic core, perfusion-diffusion mismatch and normal tissue were analyzed longitudinally. The major findings were: i) NBO treatment was effective in both groups of stroke severities, salvaging similar percentage of initial abnormal ADC tissue, and ii) NBO treatments continued after reperfusion were more beneficial than NBO treatment during occlusion alone for both MCAO groups. These findings underscore the importance of the effects of NBO duration and stroke severity on treatment outcomes.

Quantitative cerebral blood flow measurements using MRI.

Magnetic resonance imaging can be utilized as a quantitative and noninvasive method to image cerebral blood flow. The two most common techniques used to detect cerebral blood flow are dynamic susceptibility contrast (DSC) perfusion MRI and arterial spin labeling perfusion MRI. Herein we describe the use of these two techniques to measure cerebral blood flow in rodents, including methods, analysis, and important considerations when utilizing these techniques.

Characterisation of genetic variation in ST8SIA2 and its interaction region in NCAM1 in patients with bipolar disorder.

Alpha-2,8-sialyltransferase 2 (ST8SIA2) is an enzyme responsible for the transfer of polysialic acid (PSA) to glycoproteins, principally the neuronal cell adhesion molecule (NCAM1), and is involved in neuronal plasticity. Variants within ST8SIA2 have previously shown association with bipolar disorder, schizophrenia and autism. In addition, altered PSA-NCAM expression in brains of patients with schizophrenia or bipolar disorder indicates a functional dysregulation of glycosylation in mental illness. To explore the role of sequence variation affecting PSA-NCAM formation, we conducted a targeted re-sequencing study of a ∼ 100 kb region--including the entire ST8SIA2 gene and its region of interaction with NCAM1--in 48 Caucasian cases with bipolar disorder using the Roche 454 platform. We identified over 400 DNA variants, including 47 putative novel variants not described in dbSNP. Validation of a subset of variants via Sequenom showed high reliability of Roche 454 genotype calls (97% genotype concordance, with 80% of novel variants independently verified). We did not observe major loss-of-function mutations that would affect PSA-NCAM formation, either by ablating ST8SIA2 function or by affecting the ability of NCAM1 to be glycosylated. However, we identified 13 SNPs in the UTRs of ST8SIA2, a synonymous coding SNP in exon 5 (rs2305561, P207P) and many additional non-coding variants that may influence splicing or regulation of ST8SIA2 expression. We calculated nucleotide diversity within ST8SIA2 on specific haplotypes, finding that the diversity on the specific "risk" and "protective" haplotypes was lower than other non-disease-associated haplotypes, suggesting that putative functional variation may have arisen on a spectrum of haplotypes. We have identified common and novel variants (rs11074064, rs722645, 15:92961050) that exist on a spectrum of haplotypes, yet are plausible candidates for conferring the effect of risk and protective haplotypes via multiple enhancer elements. A Galaxy workflow/pipeline for sequence analysis used herein is available at: https://main.g2.bx.psu.edu/u/a-shaw-neura/p/next-generation-resources.

Rethinking schizophrenia in the context of normal neurodevelopment.

The schizophrenia brain is differentiated from the normal brain by subtle changes, with significant overlap in measures between normal and disease states. For the past 25 years, schizophrenia has increasingly been considered a neurodevelopmental disorder. This frame of reference challenges biological researchers to consider how pathological changes identified in adult brain tissue can be accounted for by aberrant developmental processes occurring during fetal, childhood, or adolescent periods. To place schizophrenia neuropathology in a neurodevelopmental context requires solid, scrutinized evidence of changes occurring during normal development of the human brain, particularly in the cortex; however, too often data on normative developmental change are selectively referenced. This paper focuses on the development of the prefrontal cortex and charts major molecular, cellular, and behavioral events on a similar time line. We first consider the time at which human cognitive abilities such as selective attention, working memory, and inhibitory control mature, emphasizing that attainment of full adult potential is a process requiring decades. We review the timing of neurogenesis, neuronal migration, white matter changes (myelination), and synapse development. We consider how molecular changes in neurotransmitter signaling pathways are altered throughout life and how they may be concomitant with cellular and cognitive changes. We end with a consideration of how the response to drugs of abuse changes with age. We conclude that the concepts around the timing of cortical neuronal migration, interneuron maturation, and synaptic regression in humans may need revision and include greater emphasis on the protracted and dynamic changes occurring in adolescence. Updating our current understanding of post-natal neurodevelopment should aid researchers in interpreting gray matter changes and derailed neurodevelopmental processes that could underlie emergence of psychosis.

Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26.

We previously identified a significant bipolar spectrum disorder linkage peak on 15q25-26 using 35 extended families with a broad clinical phenotype, including bipolar disorder (types I and II), recurrent unipolar depression and schizoaffective disorder. However, the specific gene(s) contributing to this signal had not been identified. By a fine mapping association study in an Australian case-control cohort (n = 385), we find that the sialyltransferase 8B (ST8SIA2) gene, coding for an enzyme that glycosylates proteins involved in neuronal plasticity which has previously shown association to both schizophrenia and autism, is associated with increased risk to bipolar spectrum disorder. Nominal single point association was observed with SNPs in ST8SIA2 (rs4586379, P = 0.0043; rs2168351, P = 0.0045), and a specific risk haplotype was identified (frequency: bipolar vs controls = 0.41 vs 0.31; χ(2) = 6.46, P = 0.011, OR = 1.47). Over-representation of the specific risk haplotype was also observed in an Australian schizophrenia case-control cohort (n = 256) (χ(2) = 8.41, P = 0.004, OR = 1.82). Using GWAS data from the NIMH bipolar disorder (n = 2055) and NIMH schizophrenia (n = 2550) cohorts, the equivalent haplotype was significantly over-represented in bipolar disorder (χ(2) = 5.91, P = 0.015, OR = 1.29), with the same direction of effect in schizophrenia, albeit non-significant (χ(2) = 2.3, P = 0.129, OR = 1.09). We demonstrate marked down-regulation of ST8SIA2 gene expression across human brain development and show a significant haplotype×diagnosis effect on ST8SIA2 mRNA levels in adult cortex (ANOVA: F(1,87) = 6.031, P = 0.016). These findings suggest that variation the ST8SIA2 gene is associated with increased risk to mental illness, acting to restrict neuronal plasticity and disrupt early neuronal network formation, rendering the developing and adult brain more vulnerable to secondary genetic or environmental insults.