The effect of nicotine on sensorimotor gating is modulated by a CHRNA3 polymorphism

Petrovsky, Nadine; Ettinger, Ulrich; Kessler, Henrik; Mößner, Rainald; Wolfsgruber, Steffen; Dahmen, Norbert; Maier, Wolfgang; Wagner, Michael; Quednow, Boris B.

doi:10.1007/s00213-013-3081-1

Cited by 14 publications

(9 citation statements)

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“…Further studies might investigate possible gene*gene interactions and promising candidates for the "hidden" SNPs may lay in the CHRNA3-CHRNA5-CHRNB4 gene cluster coding for α3, α5, and β4 nicotinic acetylcholine receptor (nAChR) subtypes. SNPs from this gene cluster were reliably associated with smoking behaviour [186][187][188][189][190], and also with sensorimotor gating (PPI) [191] and cognitive performance [192]. The second and maybe more appealing explanation for the present result pattern could be a gene*environment interaction, in which smoking represents a long-lasting and ongoing environmental influence.…”

Section: +mentioning

confidence: 72%

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Quednow

Brzózka

Rossner

2014

Cell. Mol. Life Sci.

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Schizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits. Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4). Haploinsufficiency of the TCF4 (formatting follows IUPAC nomenclature: TCF4 protein/protein function, Tcf4 rodent gene cDNA mRNA, TCF4 human gene cDNA mRNA) gene causes the Pitt-Hopkins syndrome-a neurodevelopmental disease characterized by severe mental retardation. Accordingly, Tcf4 null-mutant mice display developmental brain defects. TCF4-associated risk alleles are located in putative coding and non-coding regions of the gene. Hence, subtle changes at the level of gene expression might be relevant for the etiopathology of schizophrenia. Behavioural phenotypes obtained with a mouse model of slightly increased gene dosage and electrophysiological investigations with human risk-allele carriers revealed an overlapping spectrum of schizophrenia-relevant endophenotypes. Most prominently, early information processing and higher cognitive functions appear to be associated with TCF4 risk genotypes. Moreover, a recent human study unravelled gene × environment interactions between TCF4 risk alleles and smoking behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental, and, possibly, plasticity-related transcriptional programs in the CNS and changes of TCF4 expression also appear to affect brain networks important for information processing. Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis for identifying the underlying molecular mechanisms. AbstractSchizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits.Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4 behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental and possibly also plasticity related transcriptional programs in the CNS and changes of TCF4 expression appear to affect brain networks important for information processing.Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis to identify the und...

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Section: +mentioning

confidence: 72%

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Quednow

Brzózka

Rossner

2014

Cell. Mol. Life Sci.

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“… 53 Interestingly, nicotine administration essentially normalized the effects CHRNA3 genotype on PPI suggesting that nicotine may interact with CHRNA3 variants to modulate sensorimotor gating. 54 Similarly, schizophrenia-associated TCF4 risk variants also influence sensorimotor gating and interact with smoking behavior to modulate this neurophysiological response. 8 , 9 Our finding that TCF4 directly regulates transcription of the CHRNA5/A3/B4 cluster may provide a mechanistic explanation for the interaction between TCF4 common variants with smoking behavior on auditory sensorimotor gating; considered to be an endophenotype of schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

The Psychiatric Risk Gene Transcription Factor 4 (TCF4) Regulates Neurodevelopmental Pathways Associated With Schizophrenia, Autism, and Intellectual Disability

Forrest

Hill

Kavanagh

et al. 2017

Schizophrenia Bulletin

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BackgroundCommon genetic variants in and around the gene encoding transcription factor 4 (TCF4) are associated with an increased risk of schizophrenia. Conversely, rare damaging TCF4 mutations cause Pitt–Hopkins syndrome and have also been found in individuals with intellectual disability (ID) and autism spectrum disorder (ASD).MethodsChromatin immunoprecipitation and next generation sequencing were used to identify the genomic targets of TCF4. These data were integrated with expression, epigenetic and disease gene sets using a range of computational tools.ResultsWe identify 10604 TCF4 binding sites in the genome that were assigned to 5437 genes. De novo motif enrichment found that most TCF4 binding sites contained at least one E-box (5′-CAtcTG). Approximately 77% of TCF4 binding sites overlapped with the H3K27ac histone modification for active enhancers. Enrichment analysis on the set of TCF4 targets identified numerous, highly significant functional clusters for pathways including nervous system development, ion transport and signal transduction, and co-expression modules for genes associated with synaptic function and brain development. Importantly, we found that genes harboring de novo mutations in schizophrenia (P = 5.3 × 10−7), ASD (P = 2.5 × 10−4), and ID (P = 7.6 × 10−3) were also enriched among TCF4 targets. TCF4 binding sites were also found at other schizophrenia risk loci including the nicotinic acetylcholine receptor cluster, CHRNA5/CHRNA3/CHRNB4 and SETD1A.ConclusionsThese data demonstrate that TCF4 binding sites are found in a large number of neuronal genes that include many genetic risk factors for common neurodevelopmental disorders.

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“…Second, our finding of positive nicotine effects on bottom-up triggered responses in the prosaccade and CPT paradigms underscores our argument that we had sufficient power to detect beneficial effects of nicotine. Third, we previously detected positive results of a 7mg nicotine patch on different measures of attention, inhibition and cognition in similarly selected healthy adults (Kambeitz et al;Petrovsky et al 2012;Schmechtig et al 2013;Petrovsky et al 2013b;Petrovsky et al 2013a), suggesting that the dose and method of application as well as participant selection were well justified. Finally, as will be discussed in more detail below, there were effects of repeated exposure that resulted in performance improvements in various tasks, suggesting that performance was not at ceiling which would have prevented to find improvement through nicotine.…”

Section: Nicotine Effects On Task Performance and Subjective State Ramentioning

confidence: 95%

Effects of nicotine on response inhibition and interference control

et al. 2017

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Nicotine is a cholinergic agonist with known pro-cognitive effects in the domains of alerting and orienting attention. However, its effects on attentional top-down functions such as response inhibition and interference control are less well characterised. Here, we investigated the effects of 7 mg transdermal nicotine on performance on a battery of response inhibition and interference control tasks. A sample of N = 44 healthy adult non-smokers performed antisaccade, stop signal, Stroop, go/no-go, flanker, shape matching and Simon tasks, as well as the attentional network test (ANT) and a continuous performance task (CPT). Nicotine was administered in a within-subjects, double-blind, placebo-controlled design, with order of drug administration counterbalanced. Relative to placebo, nicotine led to significantly shorter reaction times on a prosaccade task and on CPT hits but did not significantly improve inhibitory or interference control performance on any task. Instead, nicotine had a negative influence in increasing the interference effect on the Simon task. Nicotine did not alter inter-individual associations between reaction times on congruent trials and error rates on incongruent trials on any task. Finally, there were effects involving order of drug administration, suggesting practice effects but also beneficial nicotine effects when the compound was administered first. Overall, our findings support previous studies showing positive effects of nicotine on basic attentional functions but do not provide direct evidence for an improvement of top-down cognitive control through acute administration of nicotine at this dose in healthy non-smokers.

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The effect of nicotine on sensorimotor gating is modulated by a CHRNA3 polymorphism

Cited by 14 publications

References 39 publications

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

The Psychiatric Risk Gene Transcription Factor 4 (TCF4) Regulates Neurodevelopmental Pathways Associated With Schizophrenia, Autism, and Intellectual Disability

Effects of nicotine on response inhibition and interference control

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