Abstract Suicidal behavior is a major health problem worldwide. The risk of suicide-related behavior is supposed to be determined by a complex interplay of sociocultural factors, psychiatric history, ...personality traits, and genetic vulnerability. Family and twin studies point towards a partial heritability of suicidal behavior. First molecular genetic studies concentrated on genes of the serotonergic system based on the biochemical evidence that serotonergic neurotransmission is implicated in this behavior. Furthermore, genes of e.g. the dopaminergic and noradrenergic neurotransmitter systems have also been the subject of investigations in this context. The aim of this article is to review molecular genetic studies in suicidal behavior beyond the serotonergic system and to emphasize findings on new genes.
Correction to: Molecular Psychiatry advance online publication, 12 July 2016; doi:10.1038/mp.2016.97 The ninth author's name was presented incorrectly. It should have been listed as LF Jarskog.
For decades treatment of schizophrenia was restricted to drugs, which mainly target positive symptoms by interfering with the dopaminergic neurotransmission. Since a large body of experimental and ...clinical data implicate that schizophrenia may primarily be a consequence of an imbalance in the glutamatergic system, specifically the networks containing GABAergic interneurons (γ-amino butyric acid), new drugs modulating glutamatergic neurotransmission are being developed. Targeting this dysfunction may follow different strategies, including application of direct or indirect NMDA (N-methyl-D-aspartate) receptor agonists or drugs modulating the function of metabotropic glutamate receptors. Meanwhile, the first substances have proven to be effective in animal models of schizophrenia and now enter the stage of clinical trials. The most promising data have been obtained in studies employing agonists of the metabotropic glutamate receptor. A choice of these substances is presented in this review.
•Peripheral cells (T-lymphocytes) permit the non-invasive investigation of receptor-mediated signaling in the brain.•The serotonin system may be implicated in the pathogenesis of ...schizophrenia.•Intracellular calcium peaks after serotonin stimulation are abnormally high in clinically stable schizophrenic patients.•Unspecific stimulation with the mitogenic PHA does not elicit abnormal responses.
Even if more extensively investigated in affective disorders, the serotonergic system is likely to be also implicated in modulating the pathogenesis of schizophrenia, where it closely interacts with the dopaminergic and glutamatergic system. To substantiate this notion, we studied the intensity and dynamics of cellular Ca2+ responses to serotonin (5-hydoxytryptamine, 5-HT) in peripheral lymphocytes taken from currently non-psychotic schizophrenic patients. To this aim, peripheral lymphocytes were freshly obtained from healthy controls and a naturalistic collective of patients with schizophrenia in remission. Intracellular Ca2+ responses were recorded in real-time by ratiometric fluorometry after 5-HT or phythaemagglutinin (PHA) stimulation, which served as an internal reference for Ca2+ responsivity to non-specific stimulation.
The intracellular Ca2+ peak early after applying the 5-HT trigger was significantly elevated in schizophrenic patients. No significant differences of Ca2+ peak levels were seen in response to stimulation with the mitogenic agent PHA, although responses to 5-HT and PHA were positively correlated in individual patients or controls. In conclusion, the serotonergic response patterns in peripheral lymphocytes from schizophrenic patients seem to be elevated, if employing sensitive tools like determination of intracellular Ca2+ responses. Our observations suggest that the participation of serotonergic neurotransmitter system in the pathogenesis of schizophrenia may deserve more interest, even if it should only act as a modulator on the main pathology in the dopaminergic and glutamatergic systems. We hope that this pilot study will prompt further studies with larger patient collectives to revisit this question.
Antagonists of the N-methyl-D-aspartate (NMDA)-type glutamate receptor induce psychosis in healthy individuals and exacerbate schizophrenia symptoms in patients. In this study we have produced an ...animal model of NMDA receptor hypofunction by chronically treating rats with low doses of the NMDA receptor antagonist MK-801. Subsequently, we performed an expression study and identified 20 genes showing altered expression in the brain of these rats compared with untreated animals. We then explored whether the human orthologs of these genes are associated with schizophrenia in the largest schizophrenia genome-wide association study published to date, and found evidence for association for 4 out of the 20 genes: SF3B1, FOXP1, DLG2 and VGLL4. Interestingly, three of these genes, FOXP1, SF3B1 and DLG2, have previously been implicated in neurodevelopmental disorders.
Deletions encompassing the X‐linked STS gene (encoding steroid sulfatase) have been observed in subjects with neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD). ...Recently, two single nucleotide polymorphisms (SNPs) within STS (rs12861247 and rs17268988) have been reported to be associated with ADHD risk and inattentive symptoms in ADHD, respectively. Using a UK sample of ADHD subjects (aged 5–18 years), we tested the hypothesis that rs12861247 is associated with ADHD risk using a case–control approach (comparing 327 ADHD cases with 358 male controls from the Wellcome Trust Case Control Consortium). Using a subset of males from the ADHD sample, we also examined whether variation within STS is associated with symptomatology/cognitive function in ADHD. We then tested whether SNPs associated with cognitive function in ADHD were also associated with cognitive function in healthy male subjects using a German sample (n = 143, aged 18–30 years), and whether STS was expressed in brain regions pertinent to ADHD pathology during development. We did not replicate the previously identified association with rs12861247. However, in ADHD males, variation at rs17268988 was associated with inattentive symptoms, while variation within STS was significantly associated with performance on three cognitive measures. Three SNPs associated with cognitive function in ADHD males were not associated with cognitive function in healthy males. STS was highly expressed in the developing cerebellar neuroepithelium, basal ganglia, thalamus, pituitary gland, hypothalamus and choroid plexus. These data suggest that genetic variants affecting STS expression and/or activity could influence the function of brain regions perturbed in ADHD.
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