Structural brain correlates of sensorimotor gating in antipsychotic-naive men with first-episode schizophrenia

Hammer, Trine Bjørg; Oranje, Bob; Skimminge, Arnold; Aggernæs, Bodil; Ebdrup, Bjørn H; Glenthøj, Birte; Baaré, William F.C.

doi:10.1503/jpn.110129

Cited by 28 publications

(22 citation statements)

References 64 publications

(86 reference statements)

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“…due to site-specific idiosyncrasies in testing) or other confounding effects that prevented detection of the endophenotype, this might greatly diminish the scientific value of such an undertaking. The present findings support the utility and fidelity of the COGS-2 multi-site platform, because the general pattern of results with PPI and its moderating factors have been detected in single-site studies by a number of different investigative groups (Aggernaes et al, 2010; Braff et al, 1978, 1999, 2001; Csomor et al, 2009; Hammer et al, 2011, 2013; Hong et al, 2007; Kishi et al, 2012; Kumari et al, 1999, 2007; Kunugi et al, 2007; Light et al, 2012; Ludewig et al, 2003; Mackeprang et al, 2002; Martinez-Gras et al, 2009; Meincke et al, 2004; Molina et al, 2011; Moriwaki et al, 2009; Oranje and Glenthoj, 2013; Preuss et al, 2011; Quednow et al, 2006; Rabin et al, 2009; Takahashi et al, 2008; Wang et al, 2013; Weike et al, 2000; Xue et al, 2012), one of which (UCSD) is represented in this study (see reference data from UCSD, Figure 5). …”

Section: Discussionsupporting

confidence: 81%

Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS

Swerdlow

Light

Sprock

et al. 2014

Schizophrenia Research

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Background Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site “COGS-2” study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data. Methods Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60 ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures. Results 884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (p<0.002), and a significant diagnosis × test site interaction. HCS > schizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures. Discussion The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia “endophenotype” of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses.

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Section: Discussionsupporting

confidence: 81%

Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS

Swerdlow

Light

Sprock

et al. 2014

Schizophrenia Research

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“…Indeed, cell adhesion molecules of the immunoglobulin superfamily, including the close homolog to L1 (CHL1), have multiple functions in the formation of normal neuronal connections during development and in synaptic function and plasticity in the adult, processes which are thought to be disrupted in intellectual disabilities and schizophrenia. Mice deficient in the CHL1 adhesion molecule show alterations of hippocampal and thalamocortical circuitry and function, as well as behavioral anomalies such as altered exploratory behavior in novel environments (Montag-Sallaz, Baarke, & Montag, 2003; Montag-Sallaz, Schachner, & Montag, 2002) and sensorimotor gating (prepulse inhibition) (Irintchev, Koch, Needham, Maness, & Schachner, 2004; Morellini, Lepsveridze, Kahler, Dityatev, & Schachner, 2007) as also reported in schizophrenia patients (Delerue & Boucart, 2012a, 2012b; Hammer et al, 2013; Ross et al, 2013; Velasques et al, 2011; Wang et al, 2013). …”

Section: Introductionmentioning

confidence: 86%

Impaired Interval Timing and Spatial–Temporal Integration in Mice Deficient in CHL1, a Gene Associated with Schizophrenia

Buhusi

Scripa

Williams

et al. 2013

Timing Time Percept

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Interval timing is crucial for decision-making and motor control and is impaired in many neuropsychiatric disorders, including schizophrenia – a neurodevelopmental disorder with a strong genetic component. Several gene mutations, polymorphisms or rare copy number variants have been associated with schizophrenia. L1 cell adhesion molecules (L1CAMs) are involved in neurodevelopmental processes, and in synaptic function and plasticity in the adult brain. Mice deficient in the Close Homolog to L1 (CHL1) adhesion molecule show alterations of hippocampal and thalamo-cortical neuroanatomy as well as deficits in sensorimotor gating and exploratory behavior. We analyzed interval timing and attentional control of temporal and spatial information in male CHL1 deficient (KO) mice and wild type (WT) controls. In a 20-s peak-interval timing procedure (standard and reversed), KO mice showed a maintained leftward shift of the response function relative to WT, indicative of a deficit in memory encoding/decoding. In trials with 2, 5, or 10-s gaps, KO mice shifted their peak times less than WT controls at longer gap durations, suggesting a decreased (attentional) effect of interruptions. In the spatial-temporal task, KO mice made more working and reference memory errors than controls, suggestive of impaired use of spatial and/or temporal information. When the duration spent on the central platform of the maze was manipulated, WT mice showed fewer spatial errors at the trained duration than at shorter or longer durations, indicative of discrimination based upon spatial-temporal integration. In contrast, performance was similar at all tested durations in KO mice, indicative of control by spatial cues, but not by temporal cues. These results suggest that CHL1 KO mice selectively attend to the more relevant cues of the task, and fail to integrate more complex spatial-temporal information, possibly as a result of reduced memory capacity related to hippocampal impairment, and altered temporal-integration mechanisms possibly due to thalamo-cortical anomalies.

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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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Structural brain correlates of sensorimotor gating in antipsychotic-naive men with first-episode schizophrenia

Cited by 28 publications

References 64 publications

Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS

Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS

Impaired Interval Timing and Spatial–Temporal Integration in Mice Deficient in CHL1, a Gene Associated with Schizophrenia

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

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