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.

Identifying molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Taken the advantages of the nematode Caenorhabditis elegans, we investigated α-adducin (add-1) in aversive olfactory associative learning and memory. Loss of add-1 function selectively impaired short- and long-term memory without causing acquisition, sensory, or motor deficits. We showed that α-adducin is required for consolidation of synaptic plasticity, for sustained synaptic increase of AMPA-type glutamate receptor (GLR-1) content and altered GLR-1 turnover dynamics. ADD-1, in a splice-form- and tissue-specific manner, controlled the storage of memories presumably through actin-capping activity. In support of the C. elegans results, genetic variability of the human ADD1 gene was significantly associated with episodic memory performance in healthy young subjects. Finally, human ADD1 expression in nematodes restored loss of C. elegans add-1 gene function. Taken together, our findings support a role for α-adducin in memory from nematodes to humans. Studying the molecular and genetic underpinnings of memory across distinct species may be helpful in the development of novel strategies to treat memory-related diseases.

BACKGROUND Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS This largest study to date exploring the genetics of memory function in ~ 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Previous genome-wide linkage studies applied the affected sib-pair design; one investigated extended pedigrees of a genetic isolate. Here, results of a genome-wide high-density linkage scan of attention-deficit/hyperactivity disorder (ADHD) using an array-based genotyping of approximately 50 K single nucleotide polymorphism (SNPs) markers are presented. We investigated eight extended pedigrees of German origin that were non-related, not part of a genetic isolate and ascertained on the basis of clinical referral. Two parametric analyses maximizing LOD scores (MOD) and a non-parametric analysis for both a broad and a narrow phenotype approach were conducted. Novel linkage loci across all families were detected at 2q35, 5q13.1, 6q22-23 and 14q12, within individual families at 18q11.2-12.3. Further linkage regions at 7q21.11, 9q22 and 16q24.1 in all families, and at 1q25.1, 1q25.3, 9q31.1-33.1, 9q33, 12p13.33, 15q11.2-13.3 and 16p12.3-12.2 in individual families replicate previous findings. High-resolution linkage mapping points to several novel candidate genes characterized by dense expression in the brain and potential impact on disorder-relevant synaptic transmission. Our study provides further evidence for common gene effects throughout different populations despite the complex multifactorial etiology of ADHD.

Cytoplasmic polyadenylation element-binding (CPEB) proteins are crucial for synaptic plasticity and memory in model organisms. A highly conserved, mammalian-specific short intronic sequence within CPEB3 has been identified as a ribozyme with self-cleavage properties. In humans, the ribozyme sequence is polymorphic and harbors a single nucleotide polymorphism that influences cleavage activity of the ribozyme. Here we show that this variation is related to performance in an episodic memory task and that the effect of the variation depends on the emotional valence of the presented material. Our data suggest a role for human CPEB3 in human episodic memory.