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Using a model of depression in which chronic social stress induces depressive-like symptoms, we investigated effects of the selective serotonin-reuptake inhibitor (SSRI) citalopram on gene expression in the dorsal raphe nucleus of male rats. Expression of tryptophan hydroxylase (TPH) protein was found to be upregulated by the stress and normalized by citalopram, while mRNAs for genes TPH 1 and 2 were differentially affected. Citalopram had no effect on serotonin transporter mRNA but reduced serotonin-1A autoreceptor mRNA in stressed animals. The SSRI prevented the stress-induced upregulation of mRNA for CREB binding protein, synaptic vesicle glycoprotein 2b and the glial N-myc downstream-regulated gene 2, but increased mRNA for neuron-specific enolase (NSE) in both stressed and unstressed animals having no effect on stress-induced upregulation of NSE protein. These findings demonstrate that in the dorsal raphe nucleus of chronically stressed rats, citalopram normalizes TPH expression and blocks stress effects on distinct genes related to neurotransmitter release and neuroplasticity.

Background Common single nucleotide polymorphisms (SNPs) explain around 50% of genetic risk underlying Autism-Spectrum-Disorder (ASD). In a previous study we showed that common functional SNPs of genes implicated in Fragile X Syndrome (FXS) were associated with ASD (Waltes et al., 2014). The FXS associated protein FMRP is regulated by the glutamatergic system, a patho-mechanism discussed for ASD. Objective We tested if functional common SNPs of glutamatergic genes were associated with ASD or ASD specific symptoms in two large ASD family cohorts (Autism Genome Project/AGP set, N=2734 families; German data set N=578 families). Since the genetic architecture between individuals with High IQ (HIQ= IQ>70) and Low IQ (LIQ= IQ≤70) differs (Vieland et al., 2010), we also split the two cohorts into high and low functioning (HIQ, LIQ) individuals. Methods 207 functional SNPs of 124 glutamatergic genes with a minor allele frequency over 5% were tested using Plink v 1.9 (DFAM) in the cohort with HIQ, LIQ and the combined cohorts, respectively. Phenotype association was studied by logistic ordinal regression correcting for gender, IQ, clinical site and population stratification. Phenotype measures were taken from the Autism Diagnostic Interview-Revised (ADI-R) scores for Social Interaction (Domain A), Verbal Communication (B1-B4; verbal individuals only), Non-Verbal Communication (Domain B2; B3; all individuals) and Repetitive Behavior (Domain C). Variants significant in both cohorts with effect sizes in the same direction were considered as replicated. Similarly, genes with any nominal significant variant in both cohorts were considered as replicated hits. Results We identified nominal significant associations of variants rs7206796 and rs3790112 (GNAO1) as well as rs3742926 (AKAP6) in both the German and the AGP LIQ cohort. In addition, significant but not overlapping SNPs of AKAP2 were identified (LIQ only). rs731826 (AKT1S1) was associated with Non Verbal Communication in the HIQ cohorts. In addition, we report 24 variants that were nominally associated with ADI-R scores in both cohorts. Genes that were involved in all five phenotypes tested were strongly related to the mTOR Pathway (e.g. genes MTOR and TSC2) or the second messenger system (e.g. G-proteins GNAS, phospholipases PLCB, protein phosphatases PPP1CA). A subset of genes was specific to each phenotype or significant in one of the subgroups (HIQ and LIQ) only. For example AKAP13 or RPS6K are associated with Verbal Communication in Low Functioning Individuals. Discussion Replication and extending previous findings we found that variants of genes that are associated with glutamate signaling, and specifically the mTOR pathway are modulators of ASD symptoms. Genes such as TSC1 or RPS6K are known to mediate glutamatergic signaling through mTOR, whereas AKAP proteins are important interactors of glutamate receptors (Sanderson et al., 2011). Both, the mTOR pathways and AKAP proteins have previously been associated with ASD (Chen et al ., 2014; Poelmans et al., 2013). Further functional analyses of glutamatergic variants are thus recommended to elucidate ASD etiology.

Background Autism spectrum disorders (ASD) are a group of genetically and phenotypically heterogeneous neurodevelopmental disorders. Common genetic variants are currently estimated to account for over 50% of ASD liability, and are also suggested to contribute to phenotypic variability. Only few studies have reported association of genetic variants with quantitative ASD phenotypes and it is unclear if different phenotypic aspects of the disorder have a distinct etiology. Here, we aim at discovering associations of common variants with ASD related phenotypes. To interpret the findings in their biological context we mapped significant variants to their genes and tested for enriched pathways and networks implicated in brain development. Methods We investigated phenotype and genotype data of 637 German trios with ASD and of the Autism Genome Project cohort (2004 families). Both cohorts were harmonized and quality checked at phenotypic (Autism Diagnostic Interview Revised, ADI-R items) and genotypic (Illumina Microarrays) level. We performed factor analysis of 28 single items of the ADI-R used in the diagnostic algorithm. To increase genetic resolution and the number of overlapping variants between the two datasets we imputed common variants with a MAF>0.05 using the “1000 Genomes” data as reference. SNPs significantly associated with the phenotype were identified using regression models corrected for ancestry, gender and IQ. Significant variants identified in both, the German and the AGP cohort, were subjected to GO-term, KEGG, and pathway enrichment analysis. Gene-regulatory modules implicated in brain development were defined by weighted gene co-expression analysis using publicly available transcriptome data of the developing human brain (brainspan.org) and tested for enrichment with the associated gene sets. Results We extracted 5 factors of the ADI-R items labeled as joint attention, social interaction and communication, non-verbal communication, repetitive sensory-motor behavior and compulsion and restricted interests. Of the 7.5M variants with a MAF > 0.05 available after imputation and quality check over 500 were associated nominally significant and replicated with each factor respectively. Analysis of the underlying genes showed that the associated GO-terms were specific for each factor and reflected directly linked biological processes such “sensory processing” for repetitive sensory-motor behavior. Finally, we present developmental time-frames specifically enriched for associated gene-sets. Discussion Our findings suggest that each ASD related phenotype is underlying a specific genetic etiology. The identification of critical periods during development further allows understanding the effects of genetic variants at specific brain-developmental and brain-regional networks. These findings thus provided a deeper insight into the complex genetic architecture of ASD and increased our understanding of mechanisms modulating ASD phenotypes

Blunted neuroendocrine and physiological responses to the selective 5-HT(1A) receptor agonist, ipsapirone, have been observed in patients with panic disorder and/or agoraphobia (PDA). In order to examine whether this hyporesponsiveness to ipsapirone is modified by pharmacological or non-pharmacological therapeutic interventions, challenges with an oral dose of ipsapirone (0.3 mg/kg) and placebo were performed in patients with PDA before and after 10 weeks of treatment with clomipramine, aerobic exercise and placebo. Before treatment, administration of ipsapirone was followed by significant increases of cortisol, anxiety and other psychopathological symptoms in comparison to the placebo challenge. In addition, a significant decrease of body temperature was observed. After the 10-week treatment period, the psychological responses to ipsapirone were significantly reduced in the clomipramine and the exercise group. In contrast, there was a non-significant trend towards higher cortisol responses after clomipramine and exercise treatment. The hypothermic response to ipsapirone was significantly reduced by clomipramine treatment. In conclusion, our results demonstrate that effective treatment of panic disorder has divergent effects on the psychological, neuroendocrine and temperature responses to ipsapirone.

Polysomnographic sleep patterns and melatonin secretion were investigated in 5 young (age 25.6 +/- 1.1 years) and 5 middle-aged (age 49.4 +/- 5.4 years) healthy male subjects after intravenous administration of 1 mg flunitrazepam and placebo in a randomized, double-blind and cross-over setting. The area under the curve (AUC) of total nocturnal melatonin plasma concentration decreased 23.3 +/- 11.5% in young subjects (P < or = 0.05) and 39.3 +/- 5.2% in middle-aged subjects (P < or = 0.05) after flunitrazepam infusion compared with placebo infusion. Differences in nocturnal peak values of melatonin were 5.4 +/- 22.0% in young subjects (not significant) and 34.0 +/- 14.7% in middle-aged subjects (p < or = 0.05). Flunitrazepam significantly (P < or = 0.05) improved sleep latency and the number of sleep stage changes in the group of all subjects. These results show that, although the benzodiazepine flunitrazepam improves sleep, it reduces the nocturnal secretion of melatonin, and therefore alters the circadian rhythm of a hormone which is supposed to play a special role in circadian sleep-wake rhythmicity.