William Byerley

Schizophrenia and nicotinic receptors

&NA; Patients with schizophrenia often cannot respond to important features of their environment and filter out irrelevant stimuli. This dysfunction could be related to an underlying defect in inhibition‐i.e., the brains ability to alter its sensitivity to repeated stimuli. One of the neuronal mechanisms responsible for such inhibitory gating involves the activation of cholinergic nicotinic receptors in the hippocampus. These receptors are diminished in many specimens of hippocampal brain tissue obtained postmortem from schizophrenic patients. In living schizophrenic patients, stimulation of cholinergic receptors by nicotine transiently restores inhibitory gating of evoked responses to sensory stimuli. Many people with schizophrenia are heavy smokers, but the properties of the nicotinic receptor favor only short‐term activation, which may explain why cigarette smoking is only a transient symptomatic remedy. This paper reviews the clinical phenomenology of inhibitory gating deficits in people with schizophrenia, the neurobiology of such gating mechanisms, and the evidence that some individuals with the disorder may have a heritable deficit in the nicotinic cholinergic receptors involved in this neurobiological function. Inhibitory gating deficits are only partly normalized by neuroleptic drugs and are thus a target for new therapeutic strategies for schizophrenia.

A combined analysis of D22S278 marker alleles in affected sib-pairs: Support for a susceptibility locus for schizophrenia at chromosome 22q12

Several groups have reported weak evidence for linkage between schizophrenia and genetic markers located on chromosome 22q using the lod score method of analysis. However these findings involved different genetic markers and methods of analysis, and so were not directly comparable. To resolve this issue we have performed a combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. This marker was chosen because it showed maximum evidence for linkage in three independent datasets (Vallada et al., Am J Med Genet 60:139-146, 1995; Polymeropoulos et al., Neuropsychiatr Genet 54:93-99, 1994; Lasseter et al., Am J Med Genet, 60:172-173, 1995. Using the affected sib-pair method as implemented by the program ESPA, the combined dataset showed 252 alleles shared compared with 188 alleles not share (chi-square 9.31, 1df, P = 0.001) where parental genotype data was completely known. When sib-pairs for whom parental data was assigned according to probability were included the number of alleles shared was 514.1 compared with 437.8 not shared (chi-square 6.12, 1df, P = 0.006). Similar results were obtained when a likelihood ratio method for sib-pair analysis was used. These results indicate that may be a susceptibility locus for schizophrenia at 22q12.

Codistribution of a sensory gating deficit and schizophrenia in multi-affected families

Because the clinical diagnosis of schizophrenia has not generally been an adequate phenotypic marker to detect the genes that convey risk for schizophrenia, efforts have been directed toward the identification of more elementary neuronal dysfunctions in schizophrenic patients and their families. Psychophysiological studies of sensory gating and selective attention suggest that defects in these brain functions are present in schizophrenic patients and some of their relatives. This study examines one of these defects in sensory gating, failure to suppress the P50 evoked response to repeated auditory stimuli. Six pedigrees, chosen because of the presence of large sibships containing several cases of schizophrenia, were studied. A mathematical model was developed to assess the familial association of the P50 defect with schizophrenia. The model preserves the quantitative nature of the data and is suitable for use in a sample with small numbers of pedigrees comprising many individuals. It is thus suitable for the evaluation of putative phenotypes in families to be studied by linkage analysis with polymorphic genetic markers. The results suggest that the P50 defect is familially associated with schizophrenia.

Measuring liability for schizophrenia using optimized antisaccade stimulus parameters

The ability to identify unaffected gene carriers within families may be crucial to the success of schizophrenia genetics studies. Data collected from three family samples (N = 365) demonstrated that poor antisaccade performance is an exceptionally promising indicator of liability for schizophrenia. A particular antisaccade task version provides large separations (5-6 sigma) between proband and normal groups. Poor antisaccade performance alone correctly identified 70% of patients in California, Utah, and Micronesia schizophrenia samples. Twenty-five to 50% of these patients nonpsychotic first-degree relatives also had poor antisaccade performance, yielding risk ratios around 20:1 for simplex and 50:1 for multiplex schizophrenia families. Poor antisaccade performance is associated with dorsolateral prefrontal cortex pathology, suggesting that dysfunction of this circuitry also may predispose individuals to developing this disease.

Evidence for a chromosome 2p13-14 schizophrenia susceptibility locus in families from Palau, Micronesia

A large multiplex schizophrenia pedigree ascertained from the Micronesian nation of Palau was genotyped with 406 microsatellite DNA markers evenly distributed throughout the genome. Assuming autosomal dominant inheritance, the highest genome-wide lod scores were found for DNA loci mapping to 2p13–14; the maximum lod score was 2.17 (theta = 0.05) at D2S441. A nonparametric APM analysis was also suggestive at D2S441 (APM score = 2.96, P = 0.011). Of the 14 affected cases in this extended family, eight share a large haplotype in this region spanning ∼11u2009cM. When 16 other families containing 65 schizophrenic cases were typed in a follow-up study of this region, the maximum lod score remained positive (maximum at D2S441 1.69, theta = 0.20). APM results also remained positive at D2S441 for all 17 families (APM score = 4.87, P = 0.0006). The linkage and haplotype sharing results provide suggestive evidence for a 2p locus predisposing to schizophrenia in a subset of families in the Palauan population.

Genome-wide multipoint linkage analyses of multiplex schizophrenia pedigrees from the oceanic nation of Palau.

The oceanic nation of Palau has been geographically and culturally isolated over most of its 2000 year history. As part of a study of the genetic basis of schizophrenia in Palau, we genotyped five large, multigenerational schizophrenia pedigrees using markers every 10 cM (CHLC/Weber screening set 6). The number of affected/unaffected individuals genotyped per family ranged from 11/21 to 5/5. Thus the pedigrees varied in their information for linkage, but each was capable of producing a substantial LOD score. We fitted a simple dominant and recessive model to these data using multipoint linkage analysis implemented by Simwalk2. Predictably, the most informative pedigrees produced the best linkage results. After genotyping additional markers in the region, one pedigree produced a LOD = 3.4 (5q distal) under the dominant model. Seven of nine schizophrenics in the pedigree, mostly 3rd–4th degree relatives, share a 15-cM, 7-marker haplotype. For a different pedigree, another promising signal occurred on distal 3q, LOD = 2.6, for the recessive model. For two other pedigrees, the best LODs were modest, slightly better than 2.0 on 5q and 9p, while the fifth pedigree produced no noteworthy linkage signal. Similar to the results for other populations, our results suggest there are multiple genes conferring liability to schizophrenia even in the small population of Palau (roughly 21u2009000 individuals) in remote Oceania.

Developmental and genetic influences on the p50 sensory gating phenotype

Evoked potentials to pairs of click stimuli were recorded from 127 subjects ranging in age from 10 to 39 years to examine the developmental course of auditory sensory gating. The ratio of the amplitude of the second response to that of the first provides a quantitative measure of auditory sensory gating. Contrary to earlier results, the distribution of P50 ratios was unchanged between children and younger adolescents (10-14 years), older adolescents (15-19 years), and adults (20-29 and 30-39 years). Included in the sample were 39 adolescent twins, allowing assessment for possible genetic effects underlying the P50 sensory gating phenotype, by comparison of the similarity of the measure in monozygotic and same-sex dizygotic twin pairs. The monozygotic twins had significantly higher similarity for the P50 ratio within each twin pair than the dizygotic twins. These results are consistent with the presence of genetic influences on the P50 sensory gating phenotype.

Use of a neurophysiological trait in linkage analysis of schizophrenia

Traditional diagnostic techniques may not provide all the information necessary to reveal the genetic causes of schizophrenia through linkage analysis. Use of neurophysiological indicator variables that are associated with the disease may increase the probability of detecting linkage. Such variables not only produce simpler phenotypes for analysis, but they also may be more proximal to the gene products involved in neurological dysfunctions underlying schizophrenia. We have used a previously characterized neurophysiological variable, the P50 evoked-auditory response, to search for chromosomal regions that may be of interest in the study of schizophrenia. Although our scan of over 300 markers did not show strong evidence for linkage to P50 in nine families, this exploratory analysis has revealed several chromosomal regions that may deserve further study.

Analysis of chromosome 18 DNA markers in multiplex pedigrees with manic depression

Six pedigrees segregating manic-depressive illness (MDI) were analyzed for linkage to 21 highly polymorphic microsatellite DNA markers on chromosome 18. These markers span almost the entire length of the chromosome, and gaps between markers are less than 20 cM. In particular, we analyzed several markers localizing to the pericentromeric region of chromosome 18 which generated lod scores suggestive of linkage in an independent study. Lod score analysis was performed and results were examined by family. One region produced positive lod scores, though at 18q23 and not in the pericentromeric region. We additionally used two nonparametric methods because the true mode of transmission of MDI is unknown; results were again somewhat suggestive for markers in the region of 18q23 but not in the pericentromeric region.

Decreased beta-adrenergic receptors in rat brain after chronic administration of the selective serotonin uptake inhibitor fluoxetine

Fluoxetine, a novel antidepressant compound that potently and selectively inhibits serotonin uptake, was chronically administered to laboratory rats. Using in vitro receptor autoradiographic techniques, we found that the binding of [3H]-dihydroalprenolol ([3H]-DHA) decreased significantly in frontal cortex layers. Analysis of saturation experiments indicated that the reduction was due to a change in number but not affinity of [3H-DHA binding sites. The data support the hypothesis that the mechanism of action of most antidepressant compounds involves a change in beta-adrenergic receptor function.