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      Sensorimotor Gating Depends on Polymorphisms of the Serotonin-2A Receptor and Catechol- O-Methyltransferase, but Not on Neuregulin-1 Arg38Gln Genotype: A Replication Study

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          Abstract

          Background

          Prepulse inhibition (PPI) of the acoustic startle response (ASR) is an operational measure of sensorimotor gating and a promising endophenotype of schizophrenia. We have recently shown that the linked serotonin-2A receptor (5-HT 2AR) A-1438 G and T102C polymorphisms modulate PPI in schizophrenia patients. Moreover, it was shown that genetic variation in the catechol- O-methyltransferase (COMT) and the neuregulin-1 (NRG-1) proteins influences PPI in schizophrenia patients and healthy volunteers. Therefore, we aimed to replicate these results and investigated the impact of the related polymorphisms on PPI in healthy human volunteers.

          Methods

          We analyzed the 5-HT 2AR A-1438 G/T102C (rs6311/rs6313), the COMT Val158Met (rs4680), and the NRG-1 Arg38Gln (rs3924999) polymorphisms, assessing startle reactivity, habituation, and PPI of ASR in 107 healthy Caucasian volunteers.

          Results

          Subjects homozygous for the 5-HT 2AR T102C-T/A-1438 G-A allele showed increased PPI levels. In particular, male subjects with the COMT Met158Met-genotype also showed elevated PPI. The NRG-1 Arg38Gln genotype did not have a significant impact on PPI. Startle reactivity was not affected by any of the investigated polymorphisms.

          Conclusions

          We confirmed in an independent sample of healthy volunteers that PPI is influenced by genetic variation in the 5-HT 2AR gene. The influence of the COMT Val158Met genotype on PPI appears to be sex-specific. These results underscore the significance of the serotonin and dopamine systems in the modulation of sensorimotor gating.

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          Most cited references 42

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          Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.

          This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.
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            Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies.

            Since the mid-1970s, cross-species translational studies of prepulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been optimized. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30-500 ms before a strong startle-inducing stimulus, and reduces the magnitude of the startle response. In humans, PPI occurs in a robust, predictable manner when the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous). This review covers three areas of interest in human PPI studies. First, we review the normal influences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopathological disorders that form a family of gating disorders. Third, we review the relatively limited but interesting and rapidly expanding literature on pharmacological influences on PPI in humans. All studies identified by a computerized literature search that addressed the three topics of this review were compiled and evaluated. The principal studies were summarized in appropriate tables. The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domains are similar across species, supporting the value of PPI studies in translational comparisons across species. The most prominent literature describing deficits in PPI in psychiatrically defined groups features schizophrenia-spectrum patients and their clinically unaffected relatives. These findings support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology involving cortico-striato-pallido-pontine circuits exhibit poor gating of motor, sensory, or cognitive information and corresponding PPI deficits. These groups include patients with obsessive compulsive disorder, Tourette's syndrome, blepharospasm, temporal lobe epilepsy with psychosis, enuresis, and perhaps posttraumatic stress disorder (PTSD). Several pharmacological manipulations have been examined for their effects on PPI in healthy human subjects. In some cases, the alterations in PPI produced by these drugs in animals correspond to similar effects in humans. Specifically, dopamine agonists disrupt and nicotine increases PPI in at least some human studies. With some other compounds, however, the effects seen in humans appear to differ from those reported in animals. For example, the PPI-increasing effects of the glutamate antagonist ketamine and the serotonin releaser MDMA in humans are opposite to the PPI-disruptive effects of these compounds in rodents. Considerable evidence supports a high degree of homology between measures of PPI in rodents and humans, consistent with the use of PPI as a cross-species measure of sensorimotor gating. Multiple investigations of PPI using a variety of methods and parameters confirm that deficits in PPI are evident in schizophrenia-spectrum patients and in certain other disorders in which gating mechanisms are disturbed. In contrast to the extensive literature on clinical populations, much more work is required to clarify the degree of correspondence between pharmacological effects on PPI in healthy humans and those reported in animals.
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              DNA from buccal swabs recruited by mail: evaluation of storage effects on long-term stability and suitability for multiplex polymerase chain reaction genotyping.

              We provide details of an inexpensive and rapid method for extraction of DNA from buccal swabs (including samples received through the mail) and from a range of other tissue samples. The procedure we have developed provides amounts of DNA adequate for several thousand polymerase chain reactions (PCRs), and we have validated its potential for long-term storage. Samples stored for > 4 years are of comparable concentration and provide as robust PCR templates as those tested immediately after extraction. The availability of this technology is of considerable significance in planning DNA banks from population collections and cohorts.
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                Author and article information

                Journal
                Biol Psychiatry
                Biol. Psychiatry
                Biological Psychiatry
                Elsevier
                0006-3223
                1873-2402
                15 September 2009
                15 September 2009
                : 66
                : 6
                : 614-620
                Affiliations
                [a ]Department of Psychiatry, University of Bonn, Germany
                [b ]University Hospital of Psychiatry, Division of Neuropsychopharmacology and Brain Imaging, University of Zurich, Switzerland
                [c ]Department of Psychology, Institute of Psychiatry and National Institute for Health Research (NIHR), Biomedical Research Centre for Mental Health, King's College London, London, United Kingdom
                [d ]Departments of Psychiatry and Psychology, Ludwig-Maximilians-University, Munich, Germany
                [e ]Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry and NIHR Biomedical Research Centre for Mental Health, King's College London, United Kingdom
                Author notes
                [* ]Address correspondence to Boris B. Quednow, Ph.D., Dipl.-Psych., University Hospital of Psychiatry, Experimental and Clinical Pharmacopsychology, Lenggstrasse 31, CH-8032 Zurich, Switzerland quednow@ 123456bli.uzh.ch
                Article
                BPS10157
                10.1016/j.biopsych.2009.05.007
                3184478
                19545856
                © 2009 Elsevier Inc.

                This document may be redistributed and reused, subject to certain conditions.

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                Research Report

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