23 January 2013. A truncated isoform of the phosphoprotein DARPP-32 is elevated in schizophrenia, bipolar disorder, and major depressive disorder, according to a new postmortem study published online January 8 in Molecular Psychiatry. Led by Barbara Lipska of the National Institutes of Mental Health in Bethesda, Maryland, the study also finds that higher transcript expression of the truncated isoform was correlated with genetic variants in DARPP-32 linked to poor cognitive functioning.
DARPP-32, or dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa, is mainly expressed in dopaminergic neurons, and is a critical mediator of dopamine function through its inhibition of protein phosphatase 1. It has also been implicated in glutamatergic signaling, and is proposed to act as an integrator of the two neurotransmitter signals (Svenningsson et al., 2004; see SRF related news story). DARPP-32 has multiple splice variants, including the full-length isoform as well as a truncated version (t-DARPP-32) that lacks the sequences critical for dopamine signaling.
Several postmortem studies have examined levels of full-length DARPP-32 in schizophrenia with mixed results—increased, decreased, and unchanged levels have all been reported (Feldcamp et al., 2008; Zhan et al., 2011)—but levels of the truncated isoform have not yet been studied. In the current report, first author Yasuto Kunii and colleagues used real-time quantitative PCR to assess the gene expression of both DARPP-32 isoforms in the dorsolateral prefrontal cortex (DLPFC), hippocampus, and caudate of a large cohort of over 700 controls and subjects with schizophrenia, bipolar disorder, and major depressive disorder.
DARPP-32 in disease and development
In the DLPFC, levels of full-length DARPP-32 transcript were increased in major depression, while the expression of t-DARPP-32 was elevated in all three psychiatric illnesses. In contrast, in the hippocampus, both isoforms were significantly elevated only in bipolar disorder. There was no change in DARPP-32 levels in the caudate in either schizophrenia or bipolar disorder, although subjects with major depression were not studied.
Although smoking increased expression levels of both isoforms in the caudate, it had no effect in the other two brain regions. There were also no effects of antipsychotics, antidepressants, or lithium in any of the brain regions, suggesting that the findings reflect the disease process and are not a consequence of treatment.
An examination of DARPP-32 expression in control brain samples from different stages of human lifespan revealed that, in the DLPFC, the full-length transcript decreased during the prenatal period, but increased throughout postnatal life. In contrast, DLPFC t-DARPP-32 increased throughout both fetal and postnatal life, similar to the trajectory of both transcripts in the hippocampus.
SNPs vary with expression
Kunii and colleagues next investigated whether single nucleotide polymorphisms (SNPs) in the DARPP-32 gene (PPP1R1B) could affect its mRNA expression. Of the 58 examined, six SNPs varied with the expression of t-DARPP-32 in the DLPFC, although no associations were found in the hippocampus or caudate. Three of the identified SNPs have previously been associated with cognitive performance and frontostriatal functioning (Meyer-Lindenberg et al., 2007; see SRF related news story). In fact, the minor alleles that were associated with higher t-DARPP-32 expression had been linked to worse cognitive functioning. Since the truncated isoform lacks domains critical for dopamine signaling, it is possible that elevated levels of t-DARPP-32 may result in a reduction of dopamine signaling that impairs cognitive function.
The authors also report that a seven-SNP haplotype that they previously associated with risk for schizophrenia in a single, family-based association analysis is linked to t-DARPP-32 but not full-length DARPP-32 transcript expression. However, this finding contradicts their earlier report that the full-length isoform expression levels were associated with the haplotype (Meyer-Lindenberg et al., 2007).
In summary, the current study provides evidence that the truncated isoform of DARPP-32 is increased in subjects with schizophrenia, bipolar disorder, and major depression in a region-specific manner and is associated with SNPs previously implicated in cognitive functioning. According to the authors, because the association of SNPs with t-DARPP-32 is found in the DLPFC but not the other brain regions, “genetic structure, although perhaps necessary, is not a sufficient factor for regulating t-DARPP-32 expression in the brain.” They suggest that epigenetic mechanisms may be involved.—Allison A. Curley.
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. Abstract