Human postmortem tissue: What quality markers matter?

102

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.

Section: Postmortem Interval (Pmi)mentioning

confidence: 99%

“…Normalization to a housekeeping gene or loading a calibrator sample onto each gel may control for some of these issues. Housekeeping genes should be carefully evaluated themselves for changes in expression in various psychiatric diagnoses (Bauer et al, 2009;Stan et al, 2006).…”

Section: Western Blot Analysesmentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

102

“…Normal controls died from the following causes: gunshot wounds, aneurysm, motor vehicle accident, and a cardiac event; schizophrenia cases died from: a gastrointestinal bleed, suicide, a cardiac event, tuberculosis, a seizure, fatty liver, asphyxiation, and antidepressant intoxication. However, agonal status has not been shown to have any effect on protein (Stan et al, 2006), and therefore is not an issue with the current investigation.…”

Section: Postmortem Brainsmentioning

confidence: 94%

Protein Markers of Neurotransmitter Synthesis and Release in Postmortem Schizophrenia Substantia Nigra

Schoonover

McCollum

Roberts

2016

The substantia nigra (SN) provides the largest dopaminergic input to the brain, projects to the striatum (the primary locus of action for antipsychotic medication), and receives GABAergic and glutamatergic inputs. This study used western blot analysis to compare protein levels of tyrosine hydroxylase (TH), glutamate decarboxylase (GAD67), and vesicular glutamate transporters (vGLUT1 and vGLUT2) in postmortem human SN in schizophrenia subjects (n = 13) and matched controls (n = 12). As a preliminary analysis, the schizophrenia group was subdivided by (1) treatment status: off medication (n = 4) or on medication (n = 9); or (2) treatment response: treatment resistant (n = 5) or treatment responsive (n = 4). The combined schizophrenia group had higher TH and GAD67 protein levels than controls (an increase of 69.6%, P = 0.01 and 19.5%, P = 0.004, respectively). When subdivided by medication status, these increases were found in the on-medication subjects (TH 88.3%, P = 0.008; GAD67 40.6%, P = 0.003). In contrast, unmedicated schizophrenia subjects had higher vGLUT2 levels than controls (an increase of 28.7%, P = 0.041), but vGLUT2 levels were similar between medicated schizophrenia subjects and controls. Treatment-resistant subjects had significantly higher TH and GAD67 levels than controls (an increase of 121.0%, P = 0.0003 and 58.7%, P = 0.004, respectively). These data suggest increases in dopamine and GABA transmission in the SN in schizophrenia, with a potential relation to treatment and response.

“…Human specimens were obtained from the Dallas Brain Collection (Stan et al, 2006). With next of kin permission, tissue samples were collected from cases examined by the Dallas County Medical Examiner's Office and the Transplant Service Center at The University of Texas Southwestern Medical Center at Dallas.…”

Section: Human Tissue Samplesmentioning

confidence: 99%

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

Dietz

Kennedy

Sun

et al. 2013

Self Cite

DFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to several stimuli including antipsychotic drugs such as haloperidol. However, the functional consequences of increased DFosB expression following antipsychotic treatment have not been explored. Here, we assessed whether DFosB induction by haloperidol mediates the positive or negative consequences or clinical-related actions of antipsychotic treatment. We show that individuals with schizophrenia who were medicated with antipsychotic drugs at their time of death display increased DFosB levels in the PFC, an effect that is replicated in rats treated chronically with haloperidol. In contrast, individuals with schizophrenia who were medication-free did not exhibit this effect. Viral-mediated overexpression of DFosB in the PFC of rodents induced cognitive deficits as measured by inhibitory avoidance, increased startle responses in prepulse inhibition tasks, and increased MK-801-induced anxiety-like behaviors. Together, these results suggest that DFosB induction in the PFC by antipsychotic treatment contributes to the deleterious effects of these drugs and not to their therapeutic actions.