To Örebro University

Introduction: Both glutamate and dopamine can influence the prefrontal cortex and formation of memories through long-term potentiation (1). The frontal cortex itself is rich in glutamatergic and dopaminergic cells (2) and has been identified as an important site for the mediation of the behavioral effects of glutamatergic and dopaminergic agents (3–5). The PPP1R1B gene influences DARPP-32 availability in the frontal lobes. A allelic carriers (rs879606), have higher enzyme activity of DARPP-32, than G carriers (6). DARPP-32 integrates dopaminergic and glutaminergic transmission (7), and DARPP-32 concentrations can further influence cortical gray matter integrity (8). The individuals' age may enhance, or attenuate the influence of genetic variation on the brain and cognitive functions, due to additional impact from neuronal processes, relating to brain maturation in younger age and brain reduction in older age. We therefore wanted to investigate the effects of the gene coding for DARPP-32 (rs879606, in PPP1R1B) on frontal cortical volumes and declarative memory (episodic recall and semantic memory).

Methods: Data was used from 61 younger and older adults (°‚ 54%), from the following regions of interest (ROIs): orbito-frontal cortex (OFC), inferior prefrontal cortex (iPFC), medial prefrontal cortex (mPFC), the superior prefrontal cortex (sPFC), and the visual cortex (VC) (the calcarine fissure; cuneus), applying Freesurfer image analysis suite. Gray matter volumes were derived from gradient echo T1-weighted images acquired by a 3-Tesla scanner (Siemens Magnetom Tim Trio), using a 32-channel head coil. A series of structural equation models with latent variables were performed to assess: (1) simple genetic effects on regional brain volumes and memory. (2) We further investigated if the individuals' age could magnify the genetic effects on brain volumes and memory performance. (3) Last, we assessed if size of regional brain volumes could mediate the relationship between the rs879606 polymorphism and declarative memory.

Results: We found that the major allelic variant (G) in the single nucleotide polymorphism (SNP): rs879606 in the PPP1R1B gene influenced both frontal gray matter volume and episodic memory (EM). Homozygous carriers of the low activity G allele had larger frontal volumes and more accurate recall of episodic information. The effect sizes were moderate for mPFC (19.1% explained variance), and OFC (14.9%) and smaller for iPFC (9.4%), and EM (5%) (moderate: >10%(9)). The gene-related difference in mPFC was moderated by age, so that younger GG carriers had larger volumes in this region, than A carriers. Regional brain volumes in the mPFC, OFC, and iPFC mediated the relationship between rs879606 and EM. No effects were present for semantic memory, the superior part of the PFC and the VC.

Conclusions: The present study replicates previous associations between cognitive performance and rs879606 (10), and shed light on the potential influence of rs879606 on structural integrity of the frontal lobes. The influence of younger age on the relationship between rs879606 and the mPFC region may reflect gene-related variation in post adolescence brain maturation. The medial part of the frontal lobes is subject to dynamic changes through young adulthood (11) and DARPP-32 can influence dendritogenesis, through glutamatergic pathways (12). The mediated effect of the frontal lobes on EM recall may reflect a pathway by which genomic differences lead to variations at cellular levels of the frontal lobes that result in change in cognition. The findings reported herein need further replication from experimental reports including direct measures of glutamate and dopamine integration to determine the specific directions of causality.