A Potential Role for a Genetic Variation of AKAP5 in Human Aggression and Anger Control

Abstract

The A-kinase-anchoring protein 5 (AKAP5), a post-synaptic multi-adaptor molecule that binds G-protein-coupled receptors and intracellular signaling molecules has been implicated in emotional processing in rodents, but its role in human emotion and behavior is up to now still not quite clear. Here, we report an association of individual differences in aggressive behavior and anger expression with a functional genetic polymorphism (Pro100Leu) in the human AKAP5 gene. Among a cohort of 527 young, healthy individuals, carriers of the less common Leu allele (15.6% allele frequency) scored significantly lower in the physical aggression domain of the Buss and Perry Aggression Questionnaire and higher in the anger control dimension of the state-trait anger expression inventory. In a functional magnetic resonance imaging experiment we could further demonstrate that AKAP5 Pro100Leu modulates the interaction of negative emotional processing and executive functions. In order to investigate implicit processes of anger control, we used the well-known flanker task to evoke processes of action monitoring and error processing and added task-irrelevant neutral or angry faces in the background of the flanker stimuli. In line with our predictions, Leu carriers showed increased activation of the anterior cingulate cortex (ACC) during emotional interference, which in turn predicted shorter reaction times and might be related to stronger control of emotional interference. Conversely, Pro homozygotes exhibited increased orbitofrontal cortex (OFC) activation during emotional interference, with no behavioral advantage. Immunohistochemistry revealed AKAP5 expression in post mortem human ACC and OFC. Our results suggest that AKAP5 Pro100Leu contributes to individual differences in human aggression and anger control. Further research is warranted to explore the detailed role of AKAP5 and its gene product in human emotion processing.

Keywords: AKAP5; aggression; anger; fMRI; genetic.

Figure 1

(A) Structure of the human AKAP5 protein with the Pro100Leu polymorphism. A, B, C, basic membrane association domains; PP2B, protein phosphatase 2B binding site; PKA, protein kinase A binding site; GPCR, G-protein-coupled receptor binding region; MAGuK, binding region for membrane-associated guanylate kinase proteins. (B) Protein structure prediction using PEP-FOLD software suggests that AKAP5 Pro100Leu substitution leads to extension of an α-helical region (depicted as red cylinder), with potential consequences on the folding of domains located downstream of the mutation. (C) Genotyping of the AKAP5 Pro100Leu polymorphism. AluI digestion of the PCR products results in two fragments (174 + 98 bp) for the Leu allele or a single fragment (272 bp) for the Pro allele. PP, Pro/Pro; PL, Pro/Leu; LL, Leu/Leu; M, DNA size marker. (D) Gender bias in the distribution of the AKAP5 Pro100Leu polymorphism. Bar plots depict percentages of Pro/Pro (P/P), Pro/Leu (P/L), and Leu/Leu (L/L) carriers, separated by gender. The Leu allele was significantly more prevalent among women.

Figure 2

Effects of AKAP5 Pro100Leu on aggression and anger. Top: in the BPAQ, AKAP5 Pro100Leu was associated with significantly lower physical aggression in Leu carriers. Bottom AKAP5 Pro100Leu also predicted higher STAXI anger control scores in Leu carriers. Bar plots depict mean test scores ± SE, separated by AKAP5 genotype.

Figure 3

Functional MRI correlates of emotional interference. (A) Schematic illustration of the experimental paradigm in Section “Materials and Methods” for details. (Note: the example face stimuli in this figure and Figure 4 are not part of the actual stimulus set used in the experiment, but were created by the authors for illustrative purposes.) (B) Leu carriers exhibited increased activation of the ACC (BA 24, extending into BA 6) for emotional vs. neutral background pictures in the incongruent condition, when compared to Pro homozygotes. Conversely, Pro homozygotes showed higher activation of the medial OFC. All activations were significant at p < 0.05, small-volume FWE-corrected for anatomical ROIs. Coordinates are in MNI space; box plots depict fitted and adjusted responses for emotional vs. neutral backgrounds in the incongruent condition, separated by genotypes; error bars depict confidence intervals obtained from Bootstrap resampling.

Figure 4

Expression of AKAP5 in the human medial frontal cortex. (A) Top, middle row: strong AKAP5 immunoreactivity was observed in pyramidal cells and a subset of interneurons in the medial anterior cingulate (BA 24, 32) and in the medial PFC/supplementary motor area (SMA, BA 6). A similar pattern was also observed in the orbitofrontal cortex (OFC, BA 11). Bottom row: positive control staining from the hippocampus and striatum confirm previous findings. (B) Western blotting confirmed AKAP5 immunoreactivity in a ∼75 kDa band in the pellet fractions of the hippocampus and in the cingulate cortex, but not in the cerebellum.