Reduction of Synaptophysin Immunoreactivity in the Prefrontal Cortex of Subjects With Schizophrenia

Glantz, Leisa A.; Lewis, David A.

doi:10.1001/archpsyc.1997.01830220065010

Cited by 287 publications

(143 citation statements)

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“…The notion of a functional DLPFC "lesion" in schizophrenia is consistent with cytoarchitectural findings of reduced dendritic arborization without evidence of a reduction in the total number of prefrontal neurons [Selemon et al, 1995]. This pattern of results suggests a reduction in interneuronal neuropil that is thought to be associated with hypoactive dopaminergic modulation of pyramidal cell activity, especially within the frontal lobes [Glantz and Lewis, 1997;Goldman-Rakic and Selemon, 1997]. Selemon and Goldman-Rakic [1999] proposed that reduced neuropil reflects a form of impoverished neuronal connectivity that "appears to be a sufficient substrate for cognitive dysfunction" and schizophrenic symptomatology (p. 17).…”

Section: Introductionsupporting

confidence: 74%

Beyond hypofrontality: A quantitative meta‐analysis of functional neuroimaging studies of working memory in schizophrenia

Glahn

Ragland

Abramoff

et al. 2005

Human Brain Mapping

552

393

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Abstract:Although there is considerable evidence that patients with schizophrenia fail to activate the dorsolateral prefrontal cortex (DLPFC) to the degree seen in normal comparison subjects when performing working memory or executive tasks, hypofrontality may be coupled with relatively increased activity in other brain regions. However, most imaging studies of working memory in schizophrenia have focused on DLPFC activity. The goal of this work is to review functional neuroimaging studies that contrasted patients with schizophrenia and healthy comparison subjects during a prototypical working memory task, the n-back paradigm, to highlight areas of hyper-and hypoactivation in schizophrenia. We utilize a quantitative metaanalysis method to review 12 imaging studies where patients with schizophrenia were contrasted with healthy comparison subjects while performing the n-back paradigm. Although we find clear support for hypofrontality, we also document consistently increased activation in anterior cingulate and left frontal pole regions in patients with schizophrenia compared to that in controls. These data suggest that whereas reduced DLPFC activation is reported consistently in patients with schizophrenia relative to healthy subjects, abnormal activation patterns are not restricted to this region, raising questions as to whether the pathophysiological dysfunction in schizophrenia is specific to the DLPFC and about the relationship between impaired performance and aberrant activation patterns. The complex pattern of hyper-and hypoactivation consistently found across studies implies that rather than focusing on DLPFC dysregulation, researchers should consider the entire network of regions involved in a given task when making inferences about the biological mechanisms of schizophrenia. Hum Brain Mapp 25:60 -69, 2005.

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Section: Introductionsupporting

confidence: 74%

Beyond hypofrontality: A quantitative meta‐analysis of functional neuroimaging studies of working memory in schizophrenia

Glahn

Ragland

Abramoff

et al. 2005

Human Brain Mapping

552

393

View full text Add to dashboard Cite

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“…Furthermore, synaptophysin has also been implicated in disorders of neurodevelopment such as schizophrenia. Evidence for reduced levels of synaptophysin in prefrontal cortex (PFC) in subjects with schizophrenia (Perrone-Bizzozero et al 1996;Glantz and Lewis 1997;Honer et al 1999;Karson et al 1999) has provided important support for the hypothesis of schizophrenia as a disorder of synaptic connectivity (Lewis and Lieberman 2000). Kim and Sheng 2004).…”

Section: Author Manuscriptmentioning

confidence: 99%

“…Slide-mounted fresh frozen tissue sections from subjects marked with an asterisk in Table 1 were used for immunohistochemical experiments, as previously described (Glantz and Lewis 1997). Three separate immunohistochemical experiments were performed for each of the subjects with one section from each subject included in each experiment.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Because synaptophysin immunoreactivity was virtually absent in the white matter of all subjects, light transmittance measurements in the white matter were used to control for possible nonspecific differences between subjects. Adjusted optical density values were calculated from the mean light transmittance values according to the equation: adjusted optical density = log (light transmittance in white matter/light transmittance in cortex), as previously described (Glantz and Lewis 1997). The adjusted optical density values were then used for comparisons between the age groups.…”

Section: Immunohistochemical Image Analysismentioning

confidence: 99%

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Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood

Glantz¹,

Gilmore²,

Hamer³

et al. 2007

Neuroscience

232

162

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Previous studies of postnatal synaptic development in human frontal cortex have shown that synaptic density rises after birth, reaches a plateau in childhood and then decreases to adult levels by late adolescence. A similar pattern has been seen in nonhuman primate cortex. These earlier studies in human cortex are limited, however, by significant age gaps in study subjects at critical inflection points of the developmental curve. Additionally, it is unclear if synaptic development occurs in different patterns in different cortical layers in prefrontal cortex (PFC). The purpose of this study was to examine synaptic density in human PFC across development by measuring two synaptic marker proteins: synaptophysin (presynaptic), and postsynaptic density-95 (PSD-95; postsynaptic). Western blotting was used to assess the relative levels of synaptophysin and PSD-95 in dorsolateral PFC of 42 subjects, distributed in age from 18 weeks gestation to 25 years. In addition, synaptophysin immunoreactivity was examined in each layer of areas 9 and 46 of PFC in 24 subjects, ranging in age from 0.1 to 25 years. Synaptophysin levels slowly increased from birth until age 5 and then increased more rapidly to peak in late childhood around age 10. Synaptophysin subsequently decreased until the adult level was reached by mid-adolescence, around age 16. PSD-95 levels increased postnatally to reach a stable plateau by early childhood with a slight reduction in late adolescence and early adulthood. The pattern of synaptophysin immunoreactivity seen with immunohistochemistry was similar to the Western experiments but the changes across age were more subtle, with little change by layer within and across age. The developmental patterns exhibited by these synaptic marker proteins expand upon previous studies of developmental synaptic changes in human frontal cortex; synaptic density increases steadily from birth to late childhood, then decreases in early adolescence to reach adult levels by late adolescence. Keywordsadolescence; development; human; synapses; pruning; synaptogenesisThe human brain has the most protracted period of development of any species, with neurodevelopment continuing well into early adulthood. Imaging studies have shown that in the human, the overall volume of the brain increases during childhood and adolescence (Giedd Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 November 9. Sowell et al. 2002;Gilmore et al. 2007). Specifically, the cortical gray matter volume, particularly the f...

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“…However, the distinctive features of such subjects constrains the extent to which findings from these studies can be generalized to other forms or earlier stages of the illness. Indeed, studies of elderly, chronically hospitalized subjects with schizophrenia have yielded some findings such as increased levels of synaptophysin protein in the prefrontal cortex (Gabriel et al 1997), that appear to be in the opposite direction to the decreased levels of this protein observed in studies of younger subjects with the disorder (Perrone-Bizzozero et al 1996;Glantz and Lewis 1997;Karson et al 1999). For most postmortem studies, especially of individuals in the early to mid-stages of a psychiatric disorder, who are most likely to die by suicide or by an accident or illness not apparently related to the primary disease process, such prospective, antemortem assessments are not possible.…”

Section: Clinical Diagnosismentioning

confidence: 99%

The Human Brain Revisited Opportunities and Challenges in Postmortem Studies of Psychiatric Disorders

Lewis

2002

Neuropsychopharmacology

186

126

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Studies of the postmortem human brain have become an increasingly essential element of the effort to understand the neurobiology of psychiatric disorders, especially in light of advances in our knowledge of functional brain circuitry and the new opportunities to apply the approaches of genomics and proteomics. This Perspective reviews some of the opportunities afforded by investigations of the postmortem human brain, and offers suggestions for improving the quality of future studies through the use of wellcharacterized brain specimens, well-constructed experimental designs and well-controlled confounds. [Neuropsychopharmacology 26:143-154, 2002] © 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. KEY WORDS : Brain banks; Clinical diagnosis; Postmortem interval; SchizophreniaResearch into the pathophysiological mechanisms operative in a number of psychiatric disorders, and the insights that those findings provide regarding pathogenetic factors and treatment approaches, have been greatly accelerated in recent years through the increasing temporal, spatial and neurochemical resolution of in vivo neuroimaging techniques. In addition, genetic and behavioral animal models have provided tractable systems for investigating the details of plausible pathophysiological mechanisms. However, neither in vivo neuroimaging nor animal models permit the direct investigation of the diseased brain tissue.Although disparaged in the past due to the limitations imposed by confounding variables and the lack of reproducible findings (Plum 1972), the use of postmortem human brain specimens in the study of psychiatric disorders has experienced new life in the past 15 years. The current interest in such studies may be traced to the confluence of several streams of thought. The first, and perhaps most critical, influence was the growing recognition in the 1960s and 1970s that major psychiatric disorders are diseases of the brain, and that at least some disorders, such as schizophrenia, are associated with altered brain anatomy (Stevens 1973;Johnstone et al. 1976). Second, the pioneering investigations, principally of schizophrenia, initiated in the 1980s by Francine Benes, Joel Kleinman, Arnold Scheibel and others, began to demonstrate that postmortem studies could incorporate the types of experimental designs and controls for potential confounds that characterized other areas of empirical study. Finally, the broad advances in our fund of knowledge in neuroscience, coupled with the development of new methods that could be applied in studies of postmortem brain tissue, created opportunities for novel and powerful probings into the pathobiology of psychiatric disorders. Indeed, based on the current demands for access to postmortem human brain specimens, the interest in these types of investigations of psychiatric disorders has never been greater. 26 , NO . 2 The direct study of the postmortem human brain provides several essential elements in the study of psychiatric disorders that are not currently, an...

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Reduction of Synaptophysin Immunoreactivity in the Prefrontal Cortex of Subjects With Schizophrenia

Cited by 287 publications

References 55 publications

Beyond hypofrontality: A quantitative meta‐analysis of functional neuroimaging studies of working memory in schizophrenia

Beyond hypofrontality: A quantitative meta‐analysis of functional neuroimaging studies of working memory in schizophrenia

Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood

The Human Brain Revisited Opportunities and Challenges in Postmortem Studies of Psychiatric Disorders

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