Identification of a genetic cluster influencing memory performance and hippocampal activity in humans

Abstract

Experimental work in animals has shown that memory formation depends on a cascade of molecular events. Here we show that variability of human memory performance is related to variability in genes encoding proteins of this signaling cascade, including the NMDA and metabotrobic glutamate receptors, adenylyl cyclase, CAMKII, PKA, and PKC. The individual profile of genetic variability in these signaling molecules correlated significantly with episodic memory performance (P < 0.00001). Moreover, functional MRI during memory formation revealed that this genetic profile correlated with activations in memory-related brain regions, including the hippocampus and parahippocampal gyrus. The present study indicates that genetic variability in the human homologues of memory-related signaling molecules contributes to interindividual differences in human memory performance and memory-related brain activations.genes ͉ molecular cascade ͉ learning D uring the last three decades, animal studies in both invertebrates and vertebrates have identified genes and signaling molecules important for memory, including protein kinases and phosphatases and transcription factors (1-5). From this work, it appears that many memory-related molecular mechanisms are conserved across species. However, it is still largely unknown whether these molecular pathways are also involved in human memory. The major reason for the lack of translation of the animal findings to humans is that pharmacological manipulation of many of these signaling molecules in humans is not feasible due to either safety issues or lack of pharmacologic specificity. Recent advances in the identification of genetic polymorphisms in the human genome (6, 7) opened, however, new avenues for the examination of complex phenotypes such as human memory. Specifically, correlating the interindividual phenotypic variability with individual patterns of genetic variability in genes relevant to the phenotype of interest can powerfully detect its underlying molecular pathways (8). In the case of human memory, this approach is particularly promising, because twin studies revealed an Ϸ50% heritability for memory traits (9, 10). In the present study, we used the behavioral genetics approach to investigate the impact of genetic variability in the human homologues of memory-related signaling molecules on episodic memory. Because functional MRI (fMRI) can visualize brain processes involved in early memory formation (11, 12), we used this technique to capture genotype effects on the early phase of episodic memory (i.e., short-term memory) and to validate the genetic findings. In addition to short-term memory-related genes, we also investigated genes implicated in the formation of long-term memory (1-5), because human short-term memory performance is affected by preexisting associative networks stored in long-term memory (13).A total of 336 healthy human subjects underwent an episodic memory task. Subjects viewed six series of five semantically unrelated nouns presented at a rate of one word per second ...

Dopaminergic Gene Polymorphisms Affect Long-term Forgetting in Old Age: Further Support for the Magnification Hypothesis

“…Given that human episodic memory is a polygenetic trait (Rasch, Papassotiropoulos, & de Quervain, 2010;de Quervain & Papassotiropoulos, 2006), future research should also consider genes related to transmitter systems that are known to interact with DA systems in influencing molecular mechanisms underlying episodic memory. Examples include GABA (Swant, Stramiello, & Wagner, 2008), glutamate (Cestari & Castellano, 1997;Mele et al, 1996), acetylcholine (Fujishiro et al, 2005), and serotonin (PradoAlcalá et al, 2003) transmitter systems, all of which decline in old age (for reviews, see Eppinger, Hämmerer, & Li, 2011;Magnusson, Brim, & Das, 2010;Rissman, De Blas, & Armstrong, 2007).…”

“…Genotypes were defined as beneficial for memory consolidation if they have been associated with higher DA transmitter content (e.g., Heinz et al, 2000), higher receptor availability (e.g., Hirvonen, Lumme, et al, 2009), or better behavioral performance (e.g., Bombin et al, 2008;Roussos, Giakoumaki, & Bitsios, 2008) in previous studies (see details below). Similar approaches using multiple genes have proven to be more predictive of the phenotypes of interest than focusing on single genes only (e.g., Hamrefors et al, 2010;de Quervain & Papassotiropoulos, 2006). To group participants, we focused on beneficial homozygous genotypes instead of alleles, as the three genes may have differential effects on the DA systems and the behavioral phenotypes.…”

Expression of a GRM3 Splice Variant is Increased in the Dorsolateral Prefrontal Cortex of Individuals Carrying a Schizophrenia Risk SNP

“…Recently, polymorphisms in GRM3 have also been associated with bipolar disorder (Fallin et al, 2005;Green et al, 2006), which shares points of genetic vulnerability with schizophrenia. Finally, SNPs in GRM3 are associated with cognitive performance in normal control subjects (de Quervain and Papassotiropoulos, 2006;Egan et al, 2004). However, the mechanisms underlying these genetic associations are unclear, since all known common SNPs within GRM3 are either noncoding or synonymous, and thus do not alter the amino-acid sequence of the translated receptor.…”

What Are the Ethical Problems Raised by the Increase of Cognitive Capabilities in the Defence Structure: The French Legal Structure, the Ethical Position of the French Military Health Service

“…Yet there is no direct and linear relation between the importance of genetic modification and the importance of its impact on behaviour (Roubertoux, 2004). Among animals relationships are shown between expression modes of the glutamatergic receptors NMDA and the mnesic capability, but studies conducted among men on the same genetic targets calculate their role in the modifications on the capabilities to mnesics at 5% (de Quervain & Papassotiropoulos, 2006;Craig & Plomin, 2006).…”