Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling is known to regulate emotional memory processes, particularly in men, epigenetic modifications of NR3C1 might affect the strength of traumatic memories. Here, we found that increased DNA methylation at the NGFI-A (nerve growth factor-induced protein A) binding site of the NR3C1 promoter was associated with less intrusive memory of the traumatic event and reduced PTSD risk in male, but not female survivors of the Rwandan genocide. NR3C1 methylation was not significantly related to hyperarousal or avoidance symptoms. We further investigated the relationship between NR3C1 methylation and memory functions in a neuroimaging study in healthy subjects. Increased NR3C1 methylation-which was associated with lower NR3C1 expression-was related to reduced picture recognition in male, but not female subjects. Furthermore, we found methylation-dependent differences in recognition memory-related brain activity in men. Together, these findings indicate that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to interindividual and gender-specific differences in memory functions and PTSD risk.

A plastic nervous system requires the ability not only to acquire and store but also to forget. Here, we report that musashi (msi-1) is necessary for time-dependent memory loss in C. elegans. Tissue-specific rescue demonstrates that MSI-1 function is necessary in the AVA interneuron. Using RNA-binding protein immunoprecipitation (IP), we found that MSI-1 binds to mRNAs of three subunits of the Arp2/3 actin branching regulator complex in vivo and downregulates ARX-1, ARX-2, and ARX-3 translation upon associative learning. The role of msi-1 in forgetting is also reflected by the persistence of learning-induced GLR-1 synaptic size increase in msi-1 mutants. We demonstrate that memory length is regulated cooperatively through the activation of adducin (add-1) and by the inhibitory effect of msi-1. Thus, a GLR-1/MSI-1/Arp2/3 pathway induces forgetting and represents a novel mechanism of memory decay by linking translational control to the structure of the actin cytoskeleton in neurons.

Summary Working memory, the capacity of actively maintaining task-relevant information during a cognitive task, is a heritable trait. Working memory deficits are characteristic for many psychiatric disorders. We performed genome-wide gene-set enrichment analyses in multiple independent data sets of young and aged cognitively healthy subjects (n = 2’824), and in a large schizophrenia case-control sample (n = 32’143). The voltage-gated cation channel activity gene-set, consisting of genes related to neuronal excitability, was robustly linked to performance in working memory-related tasks across ages, and to schizophrenia. Functional brain imaging in 707 healthy participants linked this gene-set also to working memory-related activity in the parietal cortex and the cerebellum. Gene-set analyses may help to dissect the molecular underpinnings of cognitive dimensions, brain activity and psychopathology.

WWC1 was first implicated in human cognition through a genome wide association study in 2006 that reported an association of the intronic single nucleotide polymorphism (SNP) rs17070145 with episodic memory performance. WWC1 encodes the protein KIBRA, which is almost ubiquitously expressed. Together with its binding partners, KIBRA is assumed to play a role in synaptic plasticity. T-allele carriers of SNP rs17070145 have been reported to outperform individuals that are homozygous for the C-allele in episodic memory tasks. Here we report two random effects meta-analyses testing the association of rs17070145 with episodic and working memory. All currently available population-based association studies that investigated effects of rs17070145 on episodic or working memory were included in the analyses. Where performance measures for multiple domain-specific tasks were available for a given study population, averaged effect size estimates were calculated. The performed meta-analyses relied on 17 samples that were tested for episodic memory performance (N = 8,909) and 9 samples that had performed working memory tasks (N = 4,696). We report a significant association of rs17070145 with both episodic (r = 0.068, P = 0.001) and working memory (r = 0.035, P = 0.018). In summary, our findings indicate that SNP rs17070145 located within KIBRA explains 0.5% of the variance for episodic memory tasks and 0.1% of the variance for working memory tasks in samples of primarily Caucasian background.