The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia : further evidence and meta-analysis

NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ. interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia. PostprintPeer reviewe

Cross-species models of attention-deficit/hyperactivity disorder and autism spectrum disorder : lessons from CNTNAP2, ADGRL3, and PARK2

Animal and cellular models are essential tools for all areas of biological research including neuroscience. Model systems can also be used to investigate the pathophysiology of psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this review, we provide a summary of animal and cellular models for three genes linked to ADHD and ASD in human patients - CNTNAP2, ADGRL3, and PARK2. We also highlight the strengths and weaknesses of each model system. By bringing together behavioral and neurobiological data, we demonstrate how a cross-species approach can provide integrated insights into gene function and the pathogenesis of ADHD and ASD. The knowledge gained from transgenic models will be essential to discover and validate new treatment targets for these disorders

Mass-radius relationships for exoplanets

For planets other than Earth, interpretation of the composition and structure depends largely on comparing the mass and radius with the composition expected given their distance from the parent star. The composition implies a mass-radius relation which relies heavily on equations of state calculated from electronic structure theory and measured experimentally on Earth. We lay out a method for deriving and testing equations of state, and deduce mass-radius and mass-pressure relations for key materials whose equation of state is reasonably well established, and for differentiated Fe/rock. We find that variations in the equation of state, such as may arise when extrapolating from low pressure data, can have significant effects on predicted mass- radius relations, and on planetary pressure profiles. The relations are compared with the observed masses and radii of planets and exoplanets. Kepler-10b is apparently 'Earth- like,' likely with a proportionately larger core than Earth's, nominally 2/3 of the mass of the planet. CoRoT-7b is consistent with a rocky mantle over an Fe-based core which is likely to be proportionately smaller than Earth's. GJ 1214b lies between the mass-radius curves for H2O and CH4, suggesting an 'icy' composition with a relatively large core or a relatively large proportion of H2O. CoRoT-2b is less dense than the hydrogen relation, which could be explained by an anomalously high degree of heating or by higher than assumed atmospheric opacity. HAT-P-2b is slightly denser than the mass-radius relation for hydrogen, suggesting the presence of a significant amount of matter of higher atomic number. CoRoT-3b lies close to the hydrogen relation. The pressure at the center of Kepler-10b is 1.5+1.2-1.0 TPa. The central pressure in CoRoT-7b is probably close to 0.8TPa, though may be up to 2TPa.Comment: Added more recent exoplanets. Tidied text and references. Added extra "rock" compositions. Responded to referee comment

Apparent phase transitions in finite one-dimensional sine-Gordon lattices

We study the one-dimensional sine-Gordon model as a prototype of roughening phenomena. In spite of the fact that it has been recently proven that this model can not have any phase transition [J. A. Cuesta and A. Sanchez, J. Phys. A 35, 2373 (2002)], Langevin as well as Monte Carlo simulations strongly suggest the existence of a finite temperature separating a flat from a rough phase. We explain this result by means of the transfer operator formalism and show as a consequence that sine-Gordon lattices of any practically achievable size will exhibit this apparent phase transition at unexpectedly large temperatures.Comment: 7 pages, 4 figure

Is There a Negative Interpretation Bias in Depressed Patients? An Affective Startle Modulation Study

Background/Aims: Scientists proposed that patients with depression favour negative interpretations when appraising ambiguity. As self-report measures seem prone to response bias, implicit measures of emotional valence should be additionally used. Methods: A total of 16 patients with depression and 19 controls underwent an acoustic imagery task comprising neutral and negative words, as well as ambiguous words that could be understood either way. Affective startle modulation and direct interrogation were used to assess implicit and explicit emotional valence, respectively. We expected a negative bias for ambiguous words in the patient group, resulting in augmented startle magnitudes and preference for negative interpretations of the ambiguous words in the interrogation. Results: Surprisingly, both groups preferred neutral interpretations and showed augmented startle magnitudes to ambiguous words. Furthermore, both groups displayed an emotional startle potentiation for negative words. Conclusion: In summary, our results do not confirm a negative interpretation bias or a blunted emotional response in patients with major depression. The mismatch between self-report and affective startle reaction to ambiguous targets might reflect defensive mobilization or attention effects

On the role of NOS1 ex1f-VNTR in ADHD – allelic, subgroup, and meta-analysis

Attention deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co-morbidity analysis. Our previous finding held true in the extended sample, and also meta-analysis demonstrated an association of NOS1 ex1fVNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post-mortem brain samples. These data validate the role of NOS-I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association.PostprintPeer reviewe

Exome chip analyses in adult attention deficit hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAFgreater than or equal to1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E−06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E−08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E−07); the PSD locus (P=7.58E−08) and ZCCHC4 locus (P=1.79E−06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E−05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD

Recommendations, guidelines, and best practice for the use of human induced pluripotent stem cells for neuropharmacological studies of neuropsychiatric disorders

The number of individuals suffering from neuropsychiatric disorders (NPDs) has increased worldwide, with 3 million disability-adjusted life-years calculated in 2019. Though research using various approaches including genetics, imaging, clinical and animal models has advanced our knowledge regarding NPDs, we still lack basic knowledge regarding the underlying pathophysiological mechanisms. Moreover, there is an urgent need for highly effective therapeutics for NPDs. Human induced pluripotent stem cells (hiPSCs) generated from somatic cells enabled scientists to create brain cells in a patient-specific manner. However, there are challenges to the use of hiPSCs that need to be addressed. In the current paper, consideration of best practices for neuropharmacological and neuropsychiatric research using hiPSCs will be discussed. Specifically, we provide recommendations for best practice in patient recruitment, including collecting demographic, clinical, medical (before and after treatment and response), diagnostic (including scales) and genetic data from the donors. We highlight considerations regarding donor genetics and sex, in addition to discussing biological and technical replicates. Furthermore, we present our views on selecting control groups/lines, experimental designs, and considerations for conducting neuropharmacological studies using hiPSC-based models in the context of NPDs. In doing so, we explore key issues in the field concerning reproducibility, statistical analysis, and how to translate in vitro studies into clinically relevant observations. The aim of this article is to provide a key resource for hiPSC researchers to perform robust and reproducible neuropharmacological studies, with the ultimate aim of improving identification and clinical translation of novel therapeutic drugs for NPDs