Decreased Somal Size of Deep Layer 3 Pyramidal Neurons in the Prefrontal Cortex of Subjects With Schizophrenia

Pierri, Joseph N.; Volk, Christine L. E.; Auh, Sungyoung; Sampson, Allan R.; Lewis, David A.

doi:10.1001/archpsyc.58.5.466

Cited by 235 publications

(160 citation statements)

References 56 publications

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“…This has led to studies having more subjects and better matching for tissue pH, postmortem interval, age, and sex (Webster, 2006). Another approach is to utilize dyads or triads of matched subjects, increasing the power to detect an effect (Glantz and Lewis, 1997;Pierri et al, 2001). The field is shifting away from studies with o10 subjects per group, and the increased sample sizes accord increased statistical power to detect significant changes with smaller effect sizes (Carter et al, 2007).…”

Section: Sample Size and Study Designmentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

106

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We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

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Section: Sample Size and Study Designmentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

106

View full text Add to dashboard Cite

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“…Since COMT proteins have been detected exclusively in the neuropil of the cerebral cortex (Kaplan et al, 1979;Karhunen et al, 1994;Lundstrom et al, 1995) and neurons are the primary cell population producing COMT mRNA, it is reasonable to assume that COMT is located at dendrites and/or spines in the prefrontal cortex (Matsumoto et al, 2003). Interestingly, the prefrontal cortex of patients with schizophrenia has been reported to show reduced cortical neuropil, particularly in layer II , and decreased somal size of pyramidal neurons in layer III (Pierri et al, 2001;Rajkowska et al, 1998), both of which could be related to reduced dendritic arborization. Thus, lower levels of pyramidal COMT mRNA in these external cortical layers may reflect this putative reduction of dendrites and/or spines, where COMT protein is presumably located, and may implicate catecholaminergic synapses as part of this process.…”

Section: Discussionmentioning

confidence: 99%

Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Matsumoto

Weickert

Beltaifa

et al. 2003

Neuropsychopharmacol

126

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Human prefrontal cortical neurons express catechol O-methyltransferase (COMT), an enzyme that inactivates the neurotransmitter dopamine. A functional polymorphism of COMT, Val 108/158 Met, affects prefrontal function, and the high-activity Val allele has been reported to be a genetic risk factor for schizophrenia. We used in situ hybridization histochemistry to measure mRNA levels of COMT in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia (N ¼ 14) and of normal controls (N ¼ 15). While the groups did not differ in terms of mean level of COMT mRNA, there was a significantly different laminar pattern of COMT mRNA expression in pyramidal neurons (F ¼ 2.68, df ¼ 4,108, Po0.04); patients with schizophrenia had relatively lower levels in the superficial (II/III) layers and higher levels in the intermediate/deep (IV/V) layers (Po0.01), while in controls, the expression was homogeneous across layers. Neither the mean level nor the laminar distribution of COMT mRNA was related to the Val 108/158 Met genotype, suggesting that the feedback regulation of mRNA level is not a compensation for the functional effect of the COMT polymorphism. The disease-related laminar difference of COMT expression may be involved in dysregulation of dopamine signaling circuits in the DLPFC of patients with schizophrenia.

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“…Cytoarchitectural studies have found evidence for an increase in neuronal density, 9 decrease in neuronal size, 10,11 reduced pyramidal neuron dendritic field 12,13 and decreased dendritic spine density 14,15 with similar reductions in neuronal size observed in BPD. 16 Efforts to determine the neurochemical and molecular basis for these cellular alterations have revealed abnormalities in neurotransmission, signal transduction, inhibitory interneuron function and glial cells.…”

Section: Introductionmentioning

confidence: 92%

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

et al. 2007

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There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P < 0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.

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Decreased Somal Size of Deep Layer 3 Pyramidal Neurons in the Prefrontal Cortex of Subjects With Schizophrenia

Cited by 235 publications

References 56 publications

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

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