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Kunii Y, Hyde TM, Ye T, Li C, Kolachana B, Dickinson D, Weinberger DR, Kleinman JE, Lipska BK. Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression. Mol Psychiatry. 2013 Jan 8 ; Pubmed Abstract

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Comment by:  Jamal NasirNirmal Vadgama
Submitted 8 March 2013
Posted 8 March 2013

Kunii et al. used two different TaqMan Assays (Applied Biosystems) to compare expression levels of full-length (FL) and truncated DARPP-32 (t-DARPP-32) in various regions of the brain, and detected increased expression of t-DARPP-32 in DLPFC in both schizophrenia and bipolar disorder samples compared to controls. Overexpression of genes can cause developmental abnormalities in the brain. For example, increased LIS1 expression can lead to significant brain abnormalities in humans and mice (Bi et al., 2009).

We previously showed increased expression of DARPP-32 in human DLPFC tissue from both schizophrenia (n = 33) and bipolar disorder (n = 32) samples using the same TaqMan assay (Hs00259967_ml) as above (this detects both FL-DARPP-32 and t-DARPP-32), after excluding brain weight, age of onset, postmortem interval, time in hospital, duration of illness and antipsychotics, gender, race, smoking, alcohol, drugs, suicide status, family history, insight and psychotic features as potential confounding factors (Zhan et al., 2011). After applying Bonferroni corrections to account for multiple comparisons, our findings remained significant, and after correcting for brain pH our p-values became much more significant (p <0.001 for both schizophrenia and bipolar disorder samples vs. controls [n = 34]).

Hierarchical clustering analysis of our data revealed a distinct pattern for DARPP-32 expression in comparison to other dopamine signaling genes and dopamine receptors D1-D5, although the expression of these genes appeared to be co-regulated with the exception of dopamine receptors and D2, in particular (Zhan et al., 2011). DARPP-32 expression in relation to D2 expression is strikingly different in controls but remarkably similar in schizophrenia and bipolar samples, suggesting aberrant D2-regulated expression of DARPP-32 may be an important trigger in pathogenesis.

We found increased DARPP-32 expression in DLPFC of schizophrenia and bipolar samples by using an assay that detects both FL-DARPP-32 and t-DARPP-32. We are, therefore, unable to say whether this is attributable to increased expression of FL-DARPP-32, t-DARPP-32, or both. Kunii et al. failed to find any differences in expression levels using this assay, but since they found increased expression of t-DARPP-32, this would indicate that FL-DARPP-32 expression levels have gone down in schizophrenia and bipolar samples. However, there is inevitably considerable variability between postmortem brain samples as shown in the data presented by Kunii et al. and in other studies, so this could also account for the results. Finally, it would be useful to compare the relative expression of both isoforms of the gene in the brain during various stages of development in the same patients. This might shed useful light on their respective functions.

References:

Zhan L, Kerr JR, Lafuente M-J, Maclean A, Chibalina MV, Liu B, Burke B, Bevan S, Nasir J. (2011) Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder. Neuropathology and Applied Neurobiology 37, 206-219. Abstract

Bi W, Sapir T, Shchelochkov OA, Zhang F, Withers MA, Hunter JV, Levy T, Shinder V, Peiffer DA, Gunderson KL, Nezarati MM, Shotts VA, Amato SS, Savage SK, Harris DJ, Day-Salvatore DL, Horner M, Lu XY, Sahoo T, Yanagawa Y, Beaudet AL, Cheung SW, Martinez S, Lupski JR, Reiner O. (2009) Increased LIS1 expression affects human and mouse brain development. Nat Genet. 41:168-177. Abstract

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