Novel Schizophrenia Risk Gene TCF4 Influences Verbal Learning and Memory Functioning in Schizophrenia Patients

Background: Recently, a role of the transcription factor 4 (TCF4) gene in schizophrenia has been reported in a large genome-wide association study. It has been hypothesized that TCF4 affects normal brain development and TCF4 has been related to different forms of neurodevelopmental disorders. Schizophrenia patients exhibit strong impairments of verbal declarative memory (VDM) functions. Thus, we hypothesized that the disease-associated C allele of the rs9960767 polymorphism of the TCF4 gene led to impaired VDM functioning in schizophrenia patients. Method: The TCF4 variant was genotyped in 401 schizophrenia patients. VDM functioning was measured using the Rey Auditory Verbal Learning Test (RAVLT). Results: Carriers of the C allele were less impaired in recognition compared to those carrying the AA genotype (13.76 vs. 13.06; p = 0.049). Moreover, a trend toward higher scores in patients with the risk allele was found for delayed recall (10.24 vs. 9.41; p = 0.088). The TCF4 genotype did not influence intelligence or RAVLT immediate recall or total verbal learning. Conclusion: VDM function is influenced by the TCF4 gene in schizophrenia patients. However, the elevated risk for schizophrenia is not conferred by TCF4-mediated VDM impairment. Copyright (C) 2011 S. Karger AG, Base

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response

Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development

Association of amygdala volumes with cortisol secretion in unipolar depressed patients

Major depressive disorder (MDD) is accompanied by morphological changes of brain structures which are of great importance in the neural circuitry mediating depression like the hippocampus and the amygdala. Hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system resulting in enhanced glucocorticoid secretion can often be observed during depression and has been thought to play an important role in inducing these morphological changes. We used magnetic resonance imaging to investigate alterations of amygdala and hippocampal volumes in 86 in-patients with unipolar depression and 87 healthy controls, and we then correlated amygdala and hippocampal volumes of 76 in-patients with the area under the curve of cortisol secretion in the dexamethasone/corticotropin releasing hormone (Dex/CRH) test at baseline and during short-term antidepressant therapy. In line with recently published studies both left and right amygdala volumes of patients in a first depressive episode were smaller than those of healthy controls. Patients with recurrent depressive episodes showed a reduction of hippocampal volumes, while amygdala volumes were normal. Larger left and right amygdala volumes correlated with a more pronounced reduction of HPA activity, measured by the cortisol secretion in the combined DEX/CRH test, during antidepressant therapy in patients with recurrent depressive episodes