Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition

Abstract

Dopamine-and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), encoded by PPP1R1B, is a pivotal integrator of information in dopaminoceptive neurons, regulating the response to neuroleptics, psychotomimetics, and drugs of abuse, and affecting striatal function and plasticity. Despite extensive preclinical work, there are almost no data on DARPP-32 function in humans. Here, we identify, through resequencing in 298 chromosomes, a frequent PPP1R1B haplotype predicting mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests that depend on frontostriatal function. Multimodal imaging of healthy subjects revealed an impact of the haplotype on neostriatal volume, activation, and the functional connectivity of the prefrontal cortex. The haplotype was associated with the risk for schizophrenia in 1 family-based association analysis. Our convergent results identify a prefrontal-neostriatal system affected by variation in PPP1R1B and suggest that DARPP-32 plays a pivotal role in cognitive function and possibly in the pathogenesis of schizophrenia.Introduction Dopamine-and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) was initially identified as a major target for dopamine-activated adenylyl cyclase in striatum (1). DARPP-32 acts as an amplifier of PKA-and PKG-mediated signaling when it is phosphorylated at Thr34, which converts it into an inhibitor of a multifunctional serine/threonine protein phosphatase, PP-1 (2). Conversely, phosphorylation at Thr75 by Cdk5 converts DARPP-32 into an inhibitor of PKA. Over more than 2 decades, an intense research effort has demonstrated that this dual function places DARPP-32 at a unique position as a central molecular switch, integrating multiple information streams and converging through a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones onto dopaminoceptive neurons (3). Since dopaminergic neurotransmission is critical for motivated behavior, working memory (4), and reward-related learning (5) and is implicated in, among other conditions, schizophrenia (6), alcoholism (7), Parkinson disease, and pathological gambling (8), DARPP-32 has received considerable attention not only in basic neuroscience but also in studies of the pathogenesis of these disorders and as a potential drug target. It has been shown that DARPP-32 mediates effects of D2 receptor stimulation (3), functions as a key node in a final common pathway of psychotomimetics in both frontal cortex and striatum (9), and is implicated in the mechanism of action of drugs of abuse (10).

Genetic variation in dopaminergic neuromodulation influences the ability to rapidly and flexibly adapt decisions

“…Furthermore, when investigating interindividual differences in dopaminergic neuromodulation, it is important to consider the role of other mechanisms and interindividual differences [e.g., DA transporter reuptake (13,14,17,18) or DA activity regulation at the postsynaptic site (6,7,41)] that determine dopaminergic activity. Recent interaction studies on interindividual differences in COMT and DA transporters very elegantly show that one particular metabolic pathway within the complement determinants of dopaminergic activity in the brain may not only directly affect DA function at its acting site but also indirectly affect other dopaminergic pathways via interaction effects (13,14).…”

Dopamine modulates attentional control of auditory perception: DARPP-32 (PPP1R1B) genotype effects on behavior and cortical evoked potentials

“…Effects of the DARPP-32 genotype were observed in behavioral measures reflecting the flexibility of attentional control and cortical evoked potentials associated with attention for early sensory selection (N1 amplitude) and upregulation of cortical activity for conflict resolution (N450 amplitude). At the behavioral level, the A homozygotes of this gene, who based on past evidence are characterized by higher mRNA expression and better striatal D1 receptor function (Calabresi et al, 2000;Fienberg et al, 1998;Meyer-Lindenberg et al, 2007), were more flexible in selectively attending to either ear dependent on task requirements. In contrast, any G carriers were less able to regulate their attention according to task demands.…”

“…splicing and/or expression. There is already some molecular evidence for the latter, in terms of higher mRNA expression and better striatal receptor function (Calabresi et al, 2000;Fienberg et al, 1998, Meyer-Lindenberg et al, 2007. In human, a haplotype of the DARPP-32 gene that includes the A allele of SNP rs907094 was found to be associated with higher mRNA expressions of the DARPP-32 protein isoforms (MeyerLindenberg et al, 2007).…”

“…Furthermore, variations in this polymorphism have been found to be associated with fMRI BOLD responses or ERPs in frontal brain networks implicating attention. Individuals carrying a haplotype of the DARPP-32 gene including the A allele of the rs907094 SNP showed greater changes in BOLD response in the striatum as well as greater frontal-striatal connectivity during cognitive performance, among others during attention (Meyer-Lindenberg et al, 2007). In an emotional associative memory task that implicates the frontal-hippocampal network, variations in SNPs of the DARPP-32 gene, including rs907094, were also found to be associated with higher functional connectivity between the inferior frontal gyrus and the parahippocampal gyrus (Curcic-Blake et al, 2012).…”

“…Human studies of striatal dopaminergic modulation of attention primarily investigated attentional control in the context of complex visual perception, such as video games (Koepp et al, 1998) and affective scenes (Siessmeier et al, 2006), or in the context of other cognitive processes such as Stroop interference (Vernaleken et al, 2007), visual attention as assessed by the Trail-Making test (Meyer-Lindenberg et al, 2007) and the attentional blink effect (Colzato et al, 2011). Our findings of DARPP32 genotype effects on the behavioral performance and cortical evoked potentials that reflect attentional control of auditory perception when processing competing sensory information extend these previous findings.…”