Effects of DARPP-32 Genetic Variation on Prefrontal Cortex Volume and Episodic Memory Performance.

Ninni Persson,Catharina Lavebratt,Håkan Fischer,Jonas Persson

doi:10.3389/fnins.2017.00244

Abstract

Despite evidence of a fundamental role of DARPP-32 in integrating dopamine and glutamate signaling, studies examining gene coding for DARPP-32 in relation to neural and behavioral correlates in humans are scarce. Post mortem findings suggest genotype specific expressions of DARPP-32 in the dorsal frontal lobes. Therefore, we investigated the effects of genomic variation in DARPP-32 coding on frontal lobe volumes and episodic memory. Volumetric data from the dorsolateral (DLPFC), and visual cortices (VC) were obtained from 61 younger and older adults (♀54%). The major homozygote G, T, or A genotypes in single nucleotide polymorphisms (SNPs: rs879606; rs907094; rs3764352, the two latter in complete linkage disequilibrium), at the DARPP-32 regulating PPP1R1B gene, influenced frontal gray matter volume and episodic memory (EM). Homozygous carriers of allelic variants with lower DARPP-32 expression had an overall larger prefrontal volume in addition to greater EM recall accuracy after accounting for the influence of age. The SNPs did not influence VC volume. The genetic effects on DLPFC were greater in young adults and selective to this group for EM. Our findings suggest that genomic variation maps onto individual differences in frontal brain volumes and cognitive functions. Larger DLPFC volumes were also related to better EM performance, suggesting that gene-related differences in frontal gray matter may contribute to individual differences in EM. These results need further replication from experimental and longitudinal reports to determine directions of causality.

Highlights

Both glutamate and dopamine (DA) can influence individual differences in both the recall of memories and the functions of the frontal lobes (O’Carroll and Morris, 2004) that are rich of glutamatergic and dopaminergic cells (Tseng and O’Donnell, 2004)
Activation of stimulatory D1 receptors facilitates signaling via the protein kinase A (PKA)/Thr34-DARPP-32/phosphatase 1 (PP-1) cascade, whereas activation of inhibitory D2 receptors leads to Thr75 phosphorylation and inhibition of PP-1
We investigated the effects of three single nucleotide polymorphisms (SNPs) in the gene coding for DARPP-32 on frontal cortex volume and episodic memory (EM) function, applying a neurocognitivegenetic approach (Frank and Fossella, 2011) grounded in the outlined genotype effects on dorsolateral prefrontal cortex (DLPFC) and higher order cognitive functions (Meyer-Lindenberg et al, 2007; Curcic-Blake et al, 2012)

Summary

Introduction

Both glutamate and dopamine (DA) can influence individual differences in both the recall of memories and the functions of the frontal lobes (O’Carroll and Morris, 2004) that are rich of glutamatergic and dopaminergic cells (Tseng and O’Donnell, 2004). PKA and PP1 play central roles in the integration between glutamate and dopamine signaling, as well as in regulating activity of other effector molecules (e.g., neurotransmitters; Svenningsson et al, 2004; Gould and Manji, 2005; Fernandez et al, 2006). DARPP-32 phosphorylated on Thr by cAMP-dependent PKA inhibits PP-1, likely by docking into its active site. When DARPP-32 is phosphorylated on Thr it inhibits PKA allowing PP-1 activity. Glutamate signaling integrates with dopaminergic transmission on DARPP-32 by NMDA and AMPA receptor-driven dephosphorylation of both Thr and Thr through PP-2B (Nishi et al, 1997; Greengard et al, 1999; Svenningsson et al, 2004; Gould and Manji, 2005; Fernandez et al, 2006)

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Conclusion