Searching human brain for mechanisms of psychiatric disorders. Implications for studies on schizophrenia

Berretta, Sabina; Heckers, Stephan; Beneš, Francine M.

doi:10.1016/j.schres.2014.10.019

Cited by 14 publications

(9 citation statements)

References 107 publications

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“…Studies clarifying molecular components—and confounding effects—of brain disease are essential in making meaningful, pragmatic gains in understanding and advanced treatment development. 32 Investigation of large-scale sample sets provides a powerful advantage to identify conserved biochemical signatures that may help discriminate psychiatric disease patient groups on the basis of gene expression 33 and protein modification. 1 , 6 Prior findings and our current work provide an important comparator for emerging personalized-medicine approaches identifying disease deficits via induced pluripotent stem cells (e.g., ref ( 34 )) or by in vivo neuroimaging (e.g., ref ( 18 )) with a goal to develop an integrated and accurate understanding of the healthy and diseased brain, including epigenetic regulatory components.…”

Section: Resultsmentioning

confidence: 99%

Expression of HDAC2 but Not HDAC1 Transcript Is Reduced in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Schroeder

Gilbert

Feng

et al. 2016

ACS Chem. Neurosci.

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Postmortem brain studies support dysregulated expression of the histone deacetylase enzymes, HDAC1 and HDAC2, as a central feature in diseases including schizophrenia, bipolar disorder, and depression. Our objective was to investigate HDAC expression in a large postmortem sample set representing healthy and disease brains. We used >700 well-characterized samples from patients diagnosed with schizophrenia (n = 175), major depressive disorder (n = 135), and bipolar disorder (n = 61) to measure HDAC1 and HDAC2 transcript levels by quantitative real-time PCR in dorsolateral prefrontal cortex (DLPFC) and caudate compared to control samples. HDAC expression was calculated relative to the geometric mean of β-2-microglobulin, β-glucuronidase, and β-actin. In adult-age DLPFC, HDAC2 was decreased by 34% in schizophrenia samples compared to controls (p < 10–4). HDAC2 was significantly upregulated in major depressive disorder samples by 17% versus controls (p = 0.002). Neither smoking history nor therapeutic drugs impacted HDAC2 levels and no HDAC1 patient-control differences were observed. In caudate, HDAC levels were unchanged between patient and control groups. In control DLPFC, age fetal week 14 to 97 years (n = 326), both HDAC1 and HDAC2 levels sharply declined around birth and stabilized thereafter. Using by far the largest postmortem sample set on this topic, our major finding (decreased HDAC2 transcript) showed notable specificity in disease (schizophrenia but not major depressive disorder), HDAC subtype (HDAC2 but not HDAC1) and brain region (DLPFC but not caudate). These differences shape understanding of regional components of neural circuitry in the diseased brain and set a benchmark to quantify HDAC density and distribution using in vivo neuroimaging tools.

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Section: Resultsmentioning

confidence: 99%

Expression of HDAC2 but Not HDAC1 Transcript Is Reduced in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Schroeder

Gilbert

Feng

et al. 2016

ACS Chem. Neurosci.

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“…Much of our understanding of the pathophysiology of human diseases of the brain is derived from studies on postmortem human brain tissue [10, 15, 49]. The knowledge resulting from human postmortem brain research emphasizes the importance of collecting and banking the brains of human donors in as close to a life-like state as possible to allow for an accurate study of pathophysiologic processes.…”

Section: Introductionmentioning

confidence: 99%

Perfusion fixation in brain banking: a systematic review

McFadden

Walsh

Richter

et al. 2019

acta neuropathol commun

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Background Perfusing fixatives through the cerebrovascular system is the gold standard approach in animals to prepare brain tissue for spatial biomolecular profiling, circuit tracing, and ultrastructural studies such as connectomics. Translating these discoveries to humans requires examination of postmortem autopsy brain tissue. Yet banked brain tissue is routinely prepared using immersion fixation, which is a significant barrier to optimal preservation of tissue architecture. The challenges involved in adopting perfusion fixation in brain banks and the extent to which it improves histology quality are not well defined. Methodology We searched four databases to identify studies that have performed perfusion fixation in human brain tissue and screened the references of the eligible studies to identify further studies. From the included studies, we extracted data about the methods that they used, as well as any data comparing perfusion fixation to immersion fixation. The protocol was preregistered at the Open Science Framework: https://osf.io/cv3ys/ . Results We screened 4489 abstracts, 214 full-text publications, and identified 35 studies that met our inclusion criteria, which collectively reported on the perfusion fixation of 558 human brains. We identified a wide variety of approaches to perfusion fixation, including perfusion fixation of the brain in situ and ex situ, perfusion fixation through different sets of blood vessels, and perfusion fixation with different washout solutions, fixatives, perfusion pressures, and postfixation tissue processing methods. Through a qualitative synthesis of data comparing the outcomes of perfusion and immersion fixation, we found moderate confidence evidence showing that perfusion fixation results in equal or greater subjective histology quality compared to immersion fixation of relatively large volumes of brain tissue, in an equal or shorter amount of time. Conclusions This manuscript serves as a resource for investigators interested in building upon the methods and results of previous research in designing their own perfusion fixation studies in human brains or other large animal brains. We also suggest several future research directions, such as comparing the in situ and ex situ approaches to perfusion fixation, studying the efficacy of different washout solutions, and elucidating the types of brain donors in which perfusion fixation is likely to result in higher fixation quality than immersion fixation. Electronic supplementary material The online version of this article (10.1186/s40478-019-0799-y) contains supplementary material, which is available to authorized users.

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“…Current antipsychotic drugs share their neurotransmitter targets in dopaminergic systems. Their ineffectiveness in patients with treatment-resistant symptoms suggests that other mechanisms and neurotransmitter systems may be involved, although the evidence is still preliminary (7)(8)(9)(10). Some structural neuroimaging studies suggest that treatment resistance is associated with reduced gray matter and cortical thickness (7,11,12).…”

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confidence: 99%