Sensory Gating in Schizophrenia: P50 and N100 Gating in Antipsychotic-Free Subjects at Risk, First-Episode, and Chronic Patients

Brockhaus-Dumke, Anke; Schultze‐Lutter, Frauke; Mueller, Ralf; Tendolkar, Indira; Bechdolf, Andreas; Pukrop, Ralf; Klosterkoetter, J.; Ruhrmann, Stephan

doi:10.1016/j.biopsych.2008.02.006

Cited by 201 publications

(177 citation statements)

References 43 publications

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“…Fmr1 KO mice show deficits in sensory gating and audiogenic seizures Abnormal sensory inhibition may reflect a deficit in processing and prioritizing incoming information, a feature of schizophrenic patients (Braff et al 1978;Siegel et al 1984;Brockhaus-Dumke et al 2008;Hammer et al 2013;Rihs et al 2013). Treatments with antipsychotic drugs improve those deficits in rats and humans (Curzon et al 1994;Sanchez-Morla et al 2009;Suryavanshi et al 2014).…”

Section: Fmr1 Ko Mice Show Impaired Social Interaction and Communicationmentioning

confidence: 99%

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

2014

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The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.

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Section: Fmr1 Ko Mice Show Impaired Social Interaction and Communicationmentioning

confidence: 99%

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

2014

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“…Schizophrenia patients and to a lesser extend also their unaffected first-degree relatives consistently display disrupted sensory and sensorimotor gating, commonly demonstrated by either lower P50 suppression of the auditory evoked potential (AEP) or reduced prepulse inhibition (PPI) of the acoustic startle response [88,89,[94][95][96][97][98][99][100]. Both measures have been shown to be heritable and to be disturbed before onset of the illness [101][102][103][104][105][106][107]. Although sensory (P50 suppression) and sensorimotor (PPI) gating are conceptually related and both were parallel suggested as useful endophenotypes of schizophrenia they are not equivalent and usually also not correlated [94,[108][109][110].…”

Section: Tcf4 Information Processing and Cognition: Human Studiesmentioning

confidence: 99%

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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“…Last, and inherent to virtually any large-scale studies of schizophrenia, all of our patients were medicated with a wide range of antipsychotic agents. Given that gating 49 and oddball measures 50 seem to be impaired already in very early stages including the prodromal phase, antipsychotic medication may distort the native brain responses to auditory stimuli, which in turn might have impacted on ERP features in our study, especially because some antipsychotic agents like clozapine have been reported to normalize oddball-related ERPs like the P3 to a certain extent. 51 This hypothetical confound can only be controlled for by a replication study in unmedicated schizophrenia subjects.…”

Section: Discussionmentioning

confidence: 92%

Critical Evaluation of Auditory Event-Related Potential Deficits in Schizophrenia: Evidence From Large-Scale Single-Subject Pattern Classification

Neuhaus

Popescu

Rentzsch

et al. 2013

Schizophrenia Bulletin

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Event-related potential (ERP) deficits associated with auditory oddball and click-conditioning paradigms are among the most consistent findings in schizophrenia and are discussed as potential biomarkers. However, it is unclear to what extend these ERP deficits distinguish between schizophrenia patients and healthy controls on a single-subject level, which is of high importance for potential translation to clinical routine. Here, we investigated 144 schizophrenia patients and 144 matched controls with an auditory click-conditioning/oddball paradigm. P50 and N1 gating ratios as well as target-locked N1 and P3 components were submitted to conventional general linear models and to explorative machine learning algorithms. Repeatedmeasures ANOVAs revealed significant between-group differences for the oddball-locked N1 and P3 components but not for any gating measure. Machine learning-assisted analysis achieved 77.7% balanced classification accuracy using a combination of target-locked N1 and P3 amplitudes as classifiers. The superiority of machine learning over repeated-measures analysis for classifying schizophrenia patients was in the range of about 10% as quantified by receiver operating characteristics. For the first time, our study provides large-scale single-subject classification data on auditory click-conditioning and oddball paradigms in schizophrenia. Although our study exemplifies how automated inference may substantially improve classification accuracy, our data also show that the investigated ERP measures show comparably poor discriminatory properties in single subjects, thus illustrating the need to establish either new analytical approaches for these paradigms or other paradigms to investigate the disorder.

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Sensory Gating in Schizophrenia: P50 and N100 Gating in Antipsychotic-Free Subjects at Risk, First-Episode, and Chronic Patients

Cited by 201 publications

References 43 publications

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

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

Critical Evaluation of Auditory Event-Related Potential Deficits in Schizophrenia: Evidence From Large-Scale Single-Subject Pattern Classification

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