Abstract
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.
Highlights
THE PROBLEM OF SCHIZOPHRENIASchizophrenia affects nearly every person in the world in some way
We review examples of postmortem studies that were driven by findings from clinical genetics studies, were inspired by data from preclinical studies, highlight convergent data from complimentary biochemical techniques, and inform and refine the N-methyl D-aspartate subtype glutamate (NMDA) receptor hypothesis of schizophrenia
In the remainder of this section we examine each of these factors and discuss how they are generally handled by the field
Summary
Schizophrenia affects nearly every person in the world in some way. Based on the lifetime prevalence of the illness, B1 in 100 persons has schizophrenia (Bhugra, 2005). A third way to probe for medication effects is to perform correlation analyses between the dependent measure and a measure of total lifetime exposure to the drug, typically expressed as chlorpromazine equivalents (Law et al, 2004) This approach has shortcomings as well, including the high rate of treatment noncompliance in patients with severe mental illness (Basil et al, 2006). Beads used with samples that are not precleared nonspecifically bind proteins from several subcellular compartments including ER, mitochondria, and postsynaptic densities (McCullumsmith and Meador-Woodruff, 2011) Studies employing these methods require rigorous characterization of the immunoisolation preparation, as well as positive and negative controls for each component of the assay, including primary and secondary antibodies, capture media, and detection systems. The postmortem data for PSD95 are promising, and additional studies are warranted to fully elucidate the abnormalities of PSD95 in schizophrenia
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