Epistasis between catechol- O -methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function

Abstract

Dopaminergic and glutamatergic systems are critical components responsible for prefrontal signal-to-noise tuning in working memory. Recent functional MRI (fMRI) studies of genetic variation in these systems in catechol-O-methyltransferase (COMT) and in metabotropic glutamate receptor mgluR3 (GRM3), respectively, suggest that these genes influence prefrontal physiological signalto-noise in humans. Here, using fMRI, we extend these individual gene findings to examine the combined effects of COMT and GRM3 on dissociable components of the frontoparietal working memory network. We observed an apparent epistatic interaction of these two genes on the engagement of prefrontal cortex during working memory. Specifically, the GRM3 genotype putatively associated with suboptimal glutamatergic signaling was significantly associated with inefficient prefrontal engagement and altered prefrontalparietal coupling on the background of COMT Val-homozygous genotype. Conversely, COMT Met-homozygous background mediated against the effect of GRM3 genotype. These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia.dopamine ͉ functional MRI ͉ genetics ͉ schizophrenia D opaminergic and glutamatergic abnormalities have long served as major theoretical frameworks for understanding the pathophysiology as well as pharmacology of schizophrenia and its cognitive deficits, particularly working memory (1-4). They are also central in the neural dynamics mediating sustained activity of prefrontal neurons during working memory, and in optimizing cortical signal-to-noise (5-10). Locally sustained activity of prefrontal neurons crucial in the maintenance of information during the delay period of working memory tasks (11) seems to be protected against distracters and instability by dopamine-mediated mechanisms (12). This mechanism is likely to be through dopamine D1-receptors (9) and through their role in enhancing NMDA receptor-mediated postsynaptic currents in prefrontal pyramidal neurons active during the delay period (7, 10, 13). Concurrently, D1-receptors seem to cause a tonic increase in the firing of GABAergic inhibitory interneurons, allowing a focused increase in task-relevant activity while reducing that which is not, thus optimizing signal-to-noise (14). Therefore, dopaminergic and glutamatergic (and GABAergic) systems act together in signal-to-noise tuning critical for information processing and should have important interactions of relevance at the in vivo systems level.Less is known, however, about how these molecular and singleneuron paradigms resonate in vivo during prefrontally mediated human executive and cognitive control processes (15, 16). Biophysically based neural network models suggest that the reverberatory complement of excitatory and inhibitory NMDA and dopaminergic (and GABA) mechanisms underlie both persistent activity in working memory as well as its ex...

Differential effects of COMT on gait and executive control in aging

“…Relevant to this investigation are studies that have begun to shed light on the epitasis between COMT and other genes in the context of phenotypes such as novelty seeking (Benjamin et al, 2000), extraversion (Golimbet, Alfimova, Gritsenko, & Ebstein, 2007) and the stress response (Jabbi et al, 2007). Moreover, a recent functional magnetic resonance imaging study of working memory revealed that the COMT Met homozygous genotype mediated against inefficient task related brain activations observed in the combined presence of glutamate receptor mgluR3 (GRM3) and the homozygous COMT Val genotype (Tan et al, 2007). Future studies should examine whether interactions between COMT and other genes that affect dopamine catabolism and other neurotransmitter systems influence gait in young and old individuals as well as in disease states where gait and executive functions become impaired.…”

Intermediate phenotypes in schizophrenia genetics redux: is it a no brainer?

“…38,39 These neurotransmitter systems and related candidate genes have also been implicated in schizophrenia, 40 but the mechanism by which genetic susceptibility impacts human brain function has been obscure. Neuroimaging genetics is a promising research strategy for elucidating such mechanisms, 22 and the effect of genetic variation on these component brain systems, including epistatic interactions of genes regulating various neurotransmitter systems, 41,42 has begun to translate genetic risk into systems neuroscience.…”

“…In the actual study, 47 the SNP showing the strongest clinical association was also associated with several cognitive measures and several imaging phenotypes related to the known biology of the gene, including epistasis with dopaminergic modulation. 42 Further research will be needed to refine the statistical parameters by which combinations of disease-association and intermediate phenotype tests could be extended to more genes. But it would appear that multi-staged nested strategies can be designed such that combinations of hypothesis-driven tests of sufficient power, when integrated, will give reasonably low overall false-positive call rates, while offering insights into human disease mechanisms.…”

KIBRA and CLSTN2 polymorphisms exert interactive effects on human episodic memory

“…A possible reason for these inconsistent results is that complex cognitive functions such as episodic memory are influenced by multiple genes (Lindenberger et al, 2008;McClearn, 2006;Stelzel, Basten, Montag, Reuter, & Fiebach, 2009;Tan et al, 2007;Yacubian et al, 2007). Therefore, the effect of a single gene likely depends on the background effects of other interacting genetic modifiers.…”