5 ways postmortem studies have helped psychiatric research
Psychiatric conditions such as depression, bipolar disorder and schizophrenia are evidently disorders of the brain, but exactly how brain pathology occurs is unclear. Postmortem studies are a type of neurobiological research involving the study of human tissues after death, allowing the examination of molecules directly in the brain in ways which are not yet possible in living people. Postmortem studies therefore significantly contribute to our understanding of how psychiatric conditions develop and progress.
Recent technological advances in basic neuroscience research have improved the way postmortem studies are being used to uncover clues about the biology of psychiatric conditions. The following is a summary of five ways postmortem studies have helped us to understand the development and neurobiology of mood and psychotic disorders, and generally advanced other types of psychiatric research.
1. Uncovering cell-specific pathology
One strength of postmortem research is that we are now able to prepare tissues in ways that greatly improve how much detail we can extract from individual samples. Brain tissues are complex in that the different regions of the brain are made of up different types of neurons and supporting cells, with each type of cell having different functions and molecular compositions. Cell sorting is a powerful method for revealing the processes that are specific to particular types of cells. There are several ways this can be done, many of which are becoming cheaper, easier and faster. Some examples include fluorescence-activated cell sorting and laser capture microdissection. In addition, the field is rapidly moving towards techniques which allow us to study the genome, epigenome, and transcriptome at single cell resolution. These methods have gained momentum with several postmortem research groups who are uncovering the spectrum of cell types in the brain and their individual molecular profiles, that would have otherwise been obscured by more general and broad whole-tissue approaches. Although these techniques are tricky in postmortem tissues (where the tissue has been frozen for many years and therefore we need to find ways to stabilise the cellular membrane for cell sorting), significant progress is being made in this area. These types of studies are exponentially improving our understanding of the complexity of the brain, which is critical for how we study psychiatric disorders.
2. Bigger data, bigger steps
Most “-omics” technologies can be now be applied to postmortem studies, including microarrays, transcriptomics, genomics, proteomics and epigenomics. The great thing about these techniques is that they yield big volumes of data from small amounts of sample – a valuable approach for a limited resource like postmortem tissues. In addition, these unbiased approaches can often uncover molecular targets of interest which might not have been found using a hypothesis-driven approach. The integration of omics with more traditional forms types of neuroscience techniques are proving powerful in contributing to our understanding of how these disorders emerge and progress, as well as identifying biomarkers and affected signalling pathways to be explored further.
3. Informing in vitro and in vivo work
Schizophrenia is an especially challenging condition to study, considering its complex genetic underpinnings and environmental interactions – this is unlike other disorders for which genetic studies have been at the forefront of pathological understanding. There is no “one” model of schizophrenia, with over twenty different animal models showing various schizophrenia-like behaviours. On this background, postmortem studies are particularly useful for informing possible animal or cellular models, which can then be used to explore the underlying mechanisms and consequences of molecular aberrations on behaviour, brain function or neurochemistry. An example of how schizophrenia postmortem tissues can be integrated with animal models are “man to mouse” studies. In one example, reduced levels of RPTPα and dysbindin in NMDAR–Src complexes, as well as increased PSD95 and erbB4–PSD95 associations, were detected in the postmortem dorsolateral prefrontal cortex of schizophrenia subjects. All these alterations were hypothesized to lead to reduced Src activity. By knocking out the genes for these altered proteins in mice, the authors were able to provide molecular support of Src hypoactivity in schizophrenia (Banerjee et al., 2010). Integration of postmortem studies with model systems can thus bring about huge leaps in our understanding of how molecular aberrations present in brain conditions such as schizophrenia cause flow-on effects that contribute to disease pathology.
4. Providing clues about brain development
One theory of schizophrenia is that it is a neurodevelopmental disorder, because the prodrome and symptom onset usually occurs in either late teenage years or during the early twenties. Even though it appears that the schizophrenia brain is subjected to abnormal development, it is still unclear exactly how this transpires. One of the main reasons for this is that obtaining differently aged brains which would develop schizophrenia during maturation is not possible, because there is no way to know for certain that someone will have schizophrenia until it has fully developed. However, studies in healthy developmental postmortem studies have still aided in addressing questions related to schizophrenia neurodevelopment. A prime example is Brain Cloud, produced by the LIBD who analysed genome-wide genetic, mRNA and DNA methylation data in 261 postmortem dorsolateral prefrontal cortex samples from differently aged healthy brains across the lifespan (Calantuoni et al., 2011). The data is freely available online to researchers through an online software called
5. Informing MRI studies
Investigators searching for the neuropathology of psychiatric conditions typically study the brain on a macroscopic level (using MRI) or a microscopic level (using postmortem tissues). However, integrating the two approaches can greatly improve our progress toward understanding these conditions. For example, one feature of schizophrenia is a loss of grey matter in regions such as the prefrontal cortex and hippocampus, with this loss most pronounced during adolescence (Gogtay, 2007). However what these reductions in grey matter represent cannot be answered with imaging. Postmortem studies have showed reductions spine densities on neurons in the schizophrenia brain which have reduced grey matter volume, including layer 3 pyramidal neurons of the dorsolateral prefrontal cortex (Glantz and Lewis, 2000), pyramidal neurons of the superior temporal gyrus (Sweet et al., 2009) and subicular and CA3 dendrites (Kolomeets et al., 2005; Steen, 2006). Other studies have also shown reductions in neuropil across several regions. It is possible therefore that reduction in grey matter volume identified in schizophrenia brains with imaging could be further explored with postmortem brain studies.