Schizophrenia Research Forum - A Catalyst for Creative Thinking


Siegel BI, Sengupta EJ, Edelson JR, Lewis DA, Volk DW. Elevated Viral Restriction Factor Levels in Cortical Blood Vessels in Schizophrenia. Biol Psychiatry. 2013 Sep 30 ; Pubmed Abstract

Comments on News and Primary Papers


Primary Papers: Elevated Viral Restriction Factor Levels in Cortical Blood Vessels in Schizophrenia.

Comment by:  Cynthia Shannon Weickert, SRF Advisor
Submitted 27 December 2013
Posted 27 December 2013

Delving deeper into postmortem brains may be the key to finding new therapies!

I would like to draw attention to this recent outstanding paper by Benjamin Siegel from David Volk’s laboratory, where they found a robust increase in IFITM (interferon induced transcript transmembrane protein) mRNAs in the prefrontal cortex of people with schizophrenia, with ~40 percent of the cases showing levels twice those of controls. Since one function of IFITMs are to protect cells from viral infection, one wonders if this may be the “smoking gun” that points to an increase in viral exposure at some earlier point in the person’s life, a hypothesis for the etiology of schizophrenia that has driven the research of E. Fuller Torrey throughout his career. This indeed may be the case. IFITMs are integral membrane proteins lacking an obvious enzyme domain, and even though the mechanistic role of IFITMs in normal cell function is not entirely clear, they are key players in blocking viral membrane fusion to host cell membranes. However, since IFITMs are expressed constitutively, are found in late endosomes, and their absence can lead to morphological change in cells, it is likely that IFITMs may also play other roles in non-infected cells.

Siegel and co-authors have done a good job of addressing potential confounds of postmortem brain research, and have included factors of particular relevance to this paper. They have paid attention to possible effects of infections at the time of death and to NSAID toxicology, neither of which appear to be related to the increase in IFITM mRNAs. The in-situ hybridization results and light microscopy confirmation clearly demonstrate that the IFITM labeling is confined to blood vessels in the brain (structures that resemble caterpillar-like shapes in the colorized images). This allows the authors to make the critical observation that IFITM mRNA appears to be induced in the brain blood vessels and in the majority (86 percent) of people with schizophrenia (each compared to an individually matched control subject).

Given the remarkable increase in IFITM mRNAs (up to 150 percent in a subgroup of patients), it is surprising that this change appears not to have received more attention. In fact, with further examination of gene expression changes in schizophrenia, the increase in IFITM mRNA was buried in the original list of differentially expressed genes generated by the first ever microarray study of prefrontal cortex in schizophrenia (Mirnics et al., 2000). IFITM mRNA changes were also later clearly identified as part of immune-related changes in prefrontal cortex in schizophrenia using a custom designed microarray (Arion et al., 2007). Also in 2007, a microarray study by Saetre et al., using a large collection of brains that included the Stanley Consortium collection, the Harvard Collection, and samples from the Maudsley brain bank, showed increased expression of the ITIFM genes in the prefrontal cortex (Saetre et al., 2007). Moreover, if one explores the freely available Stanley Neuropathology Consortium Integrative Database (SNCID), as Hwang and colleagues recently have (Hwang et al., 2013), one finds that IFITM mRNAs are also elevated in the thalamus (Chu, unpublished). The significant increase in IFITM mRNA in schizophrenia has also been confirmed in the hippocampus of the Stanley Array Collection by Hwang et al. (2013), who published an increase in IFITM mRNA by RNA-seq and qRT-PCR coincident in time with Siegel’s report (Hwang et al., 2013). So, although the increase in IFITM mRNAs has been known for some time, researchers have not drilled down anatomically on the findings until now. The fact that IFITM mRNA increases have been detected in multiple brain collections and occur in cortical, hippocampal, and thalamic regions is quite remarkable and signals progress and possible new directions for the field.

In the spirit of the exercise of considering the 4 C’s (cause, consequence, compensation, or confound, coined by David Lewis) when attempting to fathom neuropathology data, Siegel et al. suggest that the changes in IFITM mRNAs may be a consequence of immune-related changes (especially in IL-6) and that an IFITM mRNA increase may have further consequences related to interneurons, particularly somatostatin mRNA. We have recently reported an increase in IL-6 mRNA levels in prefrontal cortex in schizophrenia (Fillman et al., 2013) and discussed the relationship between immune factors and interneuron mRNAs (from the Sydney brain bank of the Tissue Resource Centre). In addition, Hwang et al. (2013) used a co-expression network analysis to identify a module of co-expressed genes that was associated with schizophrenia and included increased immune/inflammatory-related genes (including IFITM2 and 3) and decreased density of parvalbumin-positive neurons in the hippocampus. Thus, three different groups have linked immune changes with interneuron deficits in the schizophrenia brain.

It is tempting for the field to try to determine cause and effect here and ask, Which came first, interneuron pathology or increased immune-related events? However, I suggest that the answer to this question may result in the need for a fifth C to be added to the deliberations regarding our interpretation of postmortem brain changes: C for “cascade.” Thus, the change could be both part of the cause and part of the consequence. Further, it may not really matter which is the cause (chicken) or the consequence (egg), as they both may be part of a downward spiral toward a pathological state where immune activation can cause interneuron pathology or vice versa. While there appears to be increasing evidence linking interneuron pathology and immune-related changes, the real questions on my mind are, How could we use this knowledge to better treat patients? Will it be possible to stop this inflammatory process and/or block changes in brain blood vessels? Will we be able to stop this putative deleterious downward spiral and bring forward new immune-based treatments that offer renewed hope for patients and their families? And finally, if infection/inflammation is implicated and environmental stimuli are provoking the brain pathology in schizophrenia, then is prevention possible?

Lessons learned: We need to invest more time, effort, and living human brain power into postmortem brain research.

References:

Arion D, Unger T, Lewis DA, Levitt P, Mirnics K. Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biol Psychiatry. 2007 Oct 1;62(7):711-21. Abstract

Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron. 2000 Oct;28(1):53-67. Abstract

Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T, Cairns M, Weickert CS. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. 2013 Feb;18(2):206-14. Abstract

Hwang Y, Kim J, Shin JY, Kim JI, Seo JS, Webster MJ, Lee D, Kim S. Gene expression profiling by mRNA sequencing reveals increased expression of immune/inflammation-related genes in the hippocampus of individuals with schizophrenia. Transl Psychiatry. 2013 Oct 29;3:e321. Abstract

Saetre P, Emilsson L, Axelsson E, Kreuger J, Lindholm E, Jazin E. Inflammation-related genes up-regulated in schizophrenia brains. BMC Psychiatry. 2007 Sep 6;7:46. Abstract

View all comments by Cynthia Shannon Weickert