The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Robert Freedman - One of the best experts on this subject based on the ideXlab platform.
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Sensory gating and Alpha-7 Nicotinic Receptor gene allelic variants in schizoaffective disorder, bipolar type.
American Journal of Medical Genetics, 2006Co-Authors: Laura F Martin, Sherry Leonard, Robert Freedman, Mei-hua Hall, Jason R Tregellas, Ann OlincyAbstract:Objectives: Single nucleotide allelic variants in the promoter region of the chromosome 15 Alpha-7 acetylcholine Nicotinic Receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. Methods: P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects’ DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Results: Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. Conclusions: In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia. 2006 Wiley-Liss, Inc.
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Alpha-7 Nicotinic Receptor agonists: potential new candidates for the treatment of schizophrenia
Psychopharmacology, 2004Co-Authors: Laura F Martin, Robert FreedmanAbstract:Rationale and objective Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha_7 Nicotinic Receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia. Method This paper will review several lines of evidence implicating the Nicotinic-cholinergic, and specifically, the alpha_7 Nicotinic Receptor system in the pathology of schizophrenia and the evidence that alpha_7 Nicotinic Receptor agonists may ameliorate some of these deficits. Results Impaired auditory sensory gating has been linked to the alpha_7 Nicotinic Receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of the promoter region of this gene are more frequent in people with schizophrenia. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to Receptor desensitization. Clozapine is able to reverse auditory sensory gating impairment, probably through an alpha_7 Nicotinic Receptor mechanism, in both humans and animal models with repeated dosing. The alpha_7 Nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and improves several cognitive measures. Conclusion Alpha-7 Nicotinic Receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.
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alpha 7 Nicotinic Receptor agonists potential new candidates for the treatment of schizophrenia
Psychopharmacology, 2004Co-Authors: Laura F Martin, William R Kem, Robert FreedmanAbstract:Rationale and objective Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha7 Nicotinic Receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia.
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The genetics of sensory gating deficits in schizophrenia.
Current psychiatry reports, 2003Co-Authors: Robert Freedman, Ann Olincy, Lawrence E. Adler, Merilyne C. Waldo, Karen E. Stevens, R.g. Ross, Sherry LeonardAbstract:Sensory gating abnormalities are an early clinical symptom of schizophrenia, and are characterized by a decrease in the brain’s normal ability to inhibit the response to unimportant stimuli. Patients appear hypervigilant and have difficulty focusing their attention. A neurobiologic mechanism involved in these difficulties is Nicotinic cholinergic modulation of inhibitory neuronal activity in the hippocampus. One measure of sensory gating abnormalities, diminished inhibition of the P50 evoked response to repeated auditory stimuli, has been linked to the chromosome 15q14 locus of the Alpha-7-Nicotinic Receptor gene. This site is one of several that have shown evidence for linkage to schizophrenia, as well as to bipolar disorder, across several studies. Polymorphisms in the core promoter of the gene are associated with schizophrenia and also with diminished inhibition of the P50 response. These genetic data may identify a new pathophysiologic target for drug discovery.
Ann Olincy - One of the best experts on this subject based on the ideXlab platform.
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Sensory gating and Alpha-7 Nicotinic Receptor gene allelic variants in schizoaffective disorder, bipolar type.
American journal of medical genetics. Part B Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2007Co-Authors: Mei-hua Hall, Jason R Tregellas, Ann OlincyAbstract:Single nucleotide allelic variants in the promoter region of the chromosome 15 Alpha-7 acetylcholine Nicotinic Receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects' DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia.
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Sensory gating and Alpha-7 Nicotinic Receptor gene allelic variants in schizoaffective disorder, bipolar type.
American Journal of Medical Genetics, 2006Co-Authors: Laura F Martin, Sherry Leonard, Robert Freedman, Mei-hua Hall, Jason R Tregellas, Ann OlincyAbstract:Objectives: Single nucleotide allelic variants in the promoter region of the chromosome 15 Alpha-7 acetylcholine Nicotinic Receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. Methods: P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects’ DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Results: Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. Conclusions: In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia. 2006 Wiley-Liss, Inc.
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The genetics of sensory gating deficits in schizophrenia.
Current psychiatry reports, 2003Co-Authors: Robert Freedman, Ann Olincy, Lawrence E. Adler, Merilyne C. Waldo, Karen E. Stevens, R.g. Ross, Sherry LeonardAbstract:Sensory gating abnormalities are an early clinical symptom of schizophrenia, and are characterized by a decrease in the brain’s normal ability to inhibit the response to unimportant stimuli. Patients appear hypervigilant and have difficulty focusing their attention. A neurobiologic mechanism involved in these difficulties is Nicotinic cholinergic modulation of inhibitory neuronal activity in the hippocampus. One measure of sensory gating abnormalities, diminished inhibition of the P50 evoked response to repeated auditory stimuli, has been linked to the chromosome 15q14 locus of the Alpha-7-Nicotinic Receptor gene. This site is one of several that have shown evidence for linkage to schizophrenia, as well as to bipolar disorder, across several studies. Polymorphisms in the core promoter of the gene are associated with schizophrenia and also with diminished inhibition of the P50 response. These genetic data may identify a new pathophysiologic target for drug discovery.
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114. Ondansetron improves P50 auditory sensory gating in medicated schizophrenic patients
Biological Psychiatry, 2000Co-Authors: Lawrence E. Adler, Ann Olincy, Ellen Cawthra, Kara A. Mcrae, H.t. Nagamoto, Josette G. HarrisAbstract:P50 auditory sensory gating is impaired in schizophrenic patients. A schizophrenic patient does not show a decrease in the amplitude of the P50 waveform of the auditory evoked potential to the second of two closely paired click stimuli. In contrast, a normal control has a greatly decreased amplitude of the P50 waveform to the second stimulus. Expressed as a percentage (amplitude to the 2 stimulus/amplitude to the first stimulus 3 100), the P50 ratio is significantly higher in schizophrenic patients. This genetic deficit in inhibitory neuronal processing is mediated by the Alpha-7 Nicotinic Receptor, which is rapidly desensitizing to nicotine. Nicotine briefly ameliorates this deficit in schizophrenic patients, but the effect is usually lost after one hour. Clozapine treatment, but not conventional antipsychotic medication, improves P50 auditory gating. We hypothesized that blockade of the 5HT3 Receptor by clozapine may result in release of acetylcholine which then acts directly at the Alpha-7 Nicotinic Receptor to enhance gating. To test this hypothesis, we gave 16 mg of oral ondansetron, a selective 5HT3 Receptor antagonist, to 7 stable medicated schizophrenic outpatients in a double-blind placebo design. On two different days, the same subject had baseline auditory evoked responses recorded followed by either oral ondansetron or placebo. ERPs were recorded hourly for the next three hours. Ondansetron, but not placebo, resulted in a significant decrease in P50 ratio in these patients (Repeated measures ANOVA: F 5 21.44, d.f. 5 1, 12, p 5 0.001) that lasted significantly longer than nicotine treatment. These results support a possible role of 5HT3 antagonism in enhancing P50 gating by atypical antipsychotics.
Lawrence E. Adler - One of the best experts on this subject based on the ideXlab platform.
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Varenicline and P50 auditory gating in medicated schizophrenic patients: a pilot study.
Psychiatry research, 2009Co-Authors: Merilyne C. Waldo, Laurie Woodward, Lawrence E. AdlerAbstract:Most schizophrenic patients have a deficit in auditory sensory gating that appears to be mediated by the Alpha-7 Nicotinic Receptor. This pilot study examines the effects of varenicline, an Alpha-7 agonist, on the P50 auditory evoked potential in six schizophrenic patients. The study was canceled because of concerning side effects consistent with those reported by the FDA. However, in this small group of subjects, varenicline did not consistently enhance P50 auditory gating.
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The genetics of sensory gating deficits in schizophrenia.
Current psychiatry reports, 2003Co-Authors: Robert Freedman, Ann Olincy, Lawrence E. Adler, Merilyne C. Waldo, Karen E. Stevens, R.g. Ross, Sherry LeonardAbstract:Sensory gating abnormalities are an early clinical symptom of schizophrenia, and are characterized by a decrease in the brain’s normal ability to inhibit the response to unimportant stimuli. Patients appear hypervigilant and have difficulty focusing their attention. A neurobiologic mechanism involved in these difficulties is Nicotinic cholinergic modulation of inhibitory neuronal activity in the hippocampus. One measure of sensory gating abnormalities, diminished inhibition of the P50 evoked response to repeated auditory stimuli, has been linked to the chromosome 15q14 locus of the Alpha-7-Nicotinic Receptor gene. This site is one of several that have shown evidence for linkage to schizophrenia, as well as to bipolar disorder, across several studies. Polymorphisms in the core promoter of the gene are associated with schizophrenia and also with diminished inhibition of the P50 response. These genetic data may identify a new pathophysiologic target for drug discovery.
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114. Ondansetron improves P50 auditory sensory gating in medicated schizophrenic patients
Biological Psychiatry, 2000Co-Authors: Lawrence E. Adler, Ann Olincy, Ellen Cawthra, Kara A. Mcrae, H.t. Nagamoto, Josette G. HarrisAbstract:P50 auditory sensory gating is impaired in schizophrenic patients. A schizophrenic patient does not show a decrease in the amplitude of the P50 waveform of the auditory evoked potential to the second of two closely paired click stimuli. In contrast, a normal control has a greatly decreased amplitude of the P50 waveform to the second stimulus. Expressed as a percentage (amplitude to the 2 stimulus/amplitude to the first stimulus 3 100), the P50 ratio is significantly higher in schizophrenic patients. This genetic deficit in inhibitory neuronal processing is mediated by the Alpha-7 Nicotinic Receptor, which is rapidly desensitizing to nicotine. Nicotine briefly ameliorates this deficit in schizophrenic patients, but the effect is usually lost after one hour. Clozapine treatment, but not conventional antipsychotic medication, improves P50 auditory gating. We hypothesized that blockade of the 5HT3 Receptor by clozapine may result in release of acetylcholine which then acts directly at the Alpha-7 Nicotinic Receptor to enhance gating. To test this hypothesis, we gave 16 mg of oral ondansetron, a selective 5HT3 Receptor antagonist, to 7 stable medicated schizophrenic outpatients in a double-blind placebo design. On two different days, the same subject had baseline auditory evoked responses recorded followed by either oral ondansetron or placebo. ERPs were recorded hourly for the next three hours. Ondansetron, but not placebo, resulted in a significant decrease in P50 ratio in these patients (Repeated measures ANOVA: F 5 21.44, d.f. 5 1, 12, p 5 0.001) that lasted significantly longer than nicotine treatment. These results support a possible role of 5HT3 antagonism in enhancing P50 gating by atypical antipsychotics.
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Nicotinic Receptor Function in Schizophrenia
Schizophrenia bulletin, 1996Co-Authors: Sherry Leonard, Charles R Breese, Lawrence E. Adler, Paula C. Bickford, Catherine E. Adams, William Byerley, Hilary Coon, Jay M. Griffith, Christine L. Miller, Marina Myles-worsleyAbstract:Schizophrenia can be partially characterized by deficits in sensory processing. Biochemical, molecular, and genetic studies of one such endophenotype, the P50 auditory-evoked potential gating deficit, suggest that one of the neuronal Nicotinic Receptors, the alpha 7 Nicotinic Receptor, may function in an inhibitory neuronal pathway involved in this phenotype. The P50 deficit is normalized in nongating subjects by nicotine. Although most schizophrenia patients are heavy smokers, the effects of nicotine may be transient, as alpha 7 Receptors are known to desensitize rapidly. In an animal model of the P50 gating deficit, antagonists of the alpha 7 Nicotinic Receptor block normal gating of the second of paired auditory stimuli. Regional localization of Receptor expression includes areas known to function in sensory filtering. An inhibitory mechanism, in the hippocampus, may involve Nicotinic stimulation of gamma-aminobutyric acid (GABA)ergic interneurons, resulting in decreased response to repetitive stimuli. Expression of the alpha 7 Receptor is decreased in hippocampal brain tissue, dissected postmortem, from schizophrenia subjects. The P50 deficit is inherited in schizophrenia pedigrees, but it is not sufficient for disease development and thus represents a predisposition factor. Linkage analysis between the P50 deficit in multiplex schizophrenia pedigrees and deoxyribonucleic acid (DNA) markers throughout the genome yielded positive lod scores to DNA markers mapping to a region of chromosome 15 containing the alpha 7 Nicotinic Receptor gene. Elucidation of possible interactions of the P50 with other factors, known to be important in the etiology of the disease, is important in determining an overall pathobiology of schizophrenia.
Laura F Martin - One of the best experts on this subject based on the ideXlab platform.
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Sensory gating and Alpha-7 Nicotinic Receptor gene allelic variants in schizoaffective disorder, bipolar type.
American Journal of Medical Genetics, 2006Co-Authors: Laura F Martin, Sherry Leonard, Robert Freedman, Mei-hua Hall, Jason R Tregellas, Ann OlincyAbstract:Objectives: Single nucleotide allelic variants in the promoter region of the chromosome 15 Alpha-7 acetylcholine Nicotinic Receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. Methods: P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects’ DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Results: Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. Conclusions: In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia. 2006 Wiley-Liss, Inc.
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Alpha-7 Nicotinic Receptor agonists: potential new candidates for the treatment of schizophrenia
Psychopharmacology, 2004Co-Authors: Laura F Martin, Robert FreedmanAbstract:Rationale and objective Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha_7 Nicotinic Receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia. Method This paper will review several lines of evidence implicating the Nicotinic-cholinergic, and specifically, the alpha_7 Nicotinic Receptor system in the pathology of schizophrenia and the evidence that alpha_7 Nicotinic Receptor agonists may ameliorate some of these deficits. Results Impaired auditory sensory gating has been linked to the alpha_7 Nicotinic Receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of the promoter region of this gene are more frequent in people with schizophrenia. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to Receptor desensitization. Clozapine is able to reverse auditory sensory gating impairment, probably through an alpha_7 Nicotinic Receptor mechanism, in both humans and animal models with repeated dosing. The alpha_7 Nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and improves several cognitive measures. Conclusion Alpha-7 Nicotinic Receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.
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alpha 7 Nicotinic Receptor agonists potential new candidates for the treatment of schizophrenia
Psychopharmacology, 2004Co-Authors: Laura F Martin, William R Kem, Robert FreedmanAbstract:Rationale and objective Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha7 Nicotinic Receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia.
Sherry Leonard - One of the best experts on this subject based on the ideXlab platform.
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Sensory gating and Alpha-7 Nicotinic Receptor gene allelic variants in schizoaffective disorder, bipolar type.
American Journal of Medical Genetics, 2006Co-Authors: Laura F Martin, Sherry Leonard, Robert Freedman, Mei-hua Hall, Jason R Tregellas, Ann OlincyAbstract:Objectives: Single nucleotide allelic variants in the promoter region of the chromosome 15 Alpha-7 acetylcholine Nicotinic Receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. Methods: P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects’ DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Results: Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. Conclusions: In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia. 2006 Wiley-Liss, Inc.
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The genetics of sensory gating deficits in schizophrenia.
Current psychiatry reports, 2003Co-Authors: Robert Freedman, Ann Olincy, Lawrence E. Adler, Merilyne C. Waldo, Karen E. Stevens, R.g. Ross, Sherry LeonardAbstract:Sensory gating abnormalities are an early clinical symptom of schizophrenia, and are characterized by a decrease in the brain’s normal ability to inhibit the response to unimportant stimuli. Patients appear hypervigilant and have difficulty focusing their attention. A neurobiologic mechanism involved in these difficulties is Nicotinic cholinergic modulation of inhibitory neuronal activity in the hippocampus. One measure of sensory gating abnormalities, diminished inhibition of the P50 evoked response to repeated auditory stimuli, has been linked to the chromosome 15q14 locus of the Alpha-7-Nicotinic Receptor gene. This site is one of several that have shown evidence for linkage to schizophrenia, as well as to bipolar disorder, across several studies. Polymorphisms in the core promoter of the gene are associated with schizophrenia and also with diminished inhibition of the P50 response. These genetic data may identify a new pathophysiologic target for drug discovery.
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chromosome workshop chromosomes 11 14 and 15
American Journal of Medical Genetics, 1999Co-Authors: Nicholas John Craddock, Corinne Lendon, Sven Cichon, Rob Culverhouse, Sevilla D Deterawadleigh, Rebecca S Devon, Steve Faraone, Tatiana Foroud, Pablo V Gejman, Sherry LeonardAbstract:This report describes linkage data presented at the Workshop on Chromosomes 11, 14, and 15 at the Sixth World Congress of Psychiatric Genetics in Bonn, Germany, together with relevant linkage data submitted to the chair and co-chair, and it is presented in the context of the previous literature concerning these chromosomes. We have attempted to collate current linkage data to provide a guide to potentially interesting findings on chromosomes 11, 14, and 15 for the phenotypes of bipolar disorder, schizophrenia, alcoholism, autism, and spelling and reading disability. We discuss methodological limitations and provide chromosome ideograms and tables summarizing findings to date. The most promising region currently appears to be 15q13-q15 in the region of the alpha 7 Nicotinic Receptor for the phenotype of schizophrenia (and, perhaps, more generally for functional psychosis). Additionally, 15q11-q13 in the region of GABRB3 holds interest as a potential site of a susceptibility gene for autism. Two regions on chromosome 11, 11p15 in the region of tyrosine hydroxylase gene and 11q22-q23 in the region of DRD2, continue to retain some interest for functional psychosis.
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Nicotinic Receptor Function in Schizophrenia
Schizophrenia bulletin, 1996Co-Authors: Sherry Leonard, Charles R Breese, Lawrence E. Adler, Paula C. Bickford, Catherine E. Adams, William Byerley, Hilary Coon, Jay M. Griffith, Christine L. Miller, Marina Myles-worsleyAbstract:Schizophrenia can be partially characterized by deficits in sensory processing. Biochemical, molecular, and genetic studies of one such endophenotype, the P50 auditory-evoked potential gating deficit, suggest that one of the neuronal Nicotinic Receptors, the alpha 7 Nicotinic Receptor, may function in an inhibitory neuronal pathway involved in this phenotype. The P50 deficit is normalized in nongating subjects by nicotine. Although most schizophrenia patients are heavy smokers, the effects of nicotine may be transient, as alpha 7 Receptors are known to desensitize rapidly. In an animal model of the P50 gating deficit, antagonists of the alpha 7 Nicotinic Receptor block normal gating of the second of paired auditory stimuli. Regional localization of Receptor expression includes areas known to function in sensory filtering. An inhibitory mechanism, in the hippocampus, may involve Nicotinic stimulation of gamma-aminobutyric acid (GABA)ergic interneurons, resulting in decreased response to repetitive stimuli. Expression of the alpha 7 Receptor is decreased in hippocampal brain tissue, dissected postmortem, from schizophrenia subjects. The P50 deficit is inherited in schizophrenia pedigrees, but it is not sufficient for disease development and thus represents a predisposition factor. Linkage analysis between the P50 deficit in multiplex schizophrenia pedigrees and deoxyribonucleic acid (DNA) markers throughout the genome yielded positive lod scores to DNA markers mapping to a region of chromosome 15 containing the alpha 7 Nicotinic Receptor gene. Elucidation of possible interactions of the P50 with other factors, known to be important in the etiology of the disease, is important in determining an overall pathobiology of schizophrenia.