SA55 - NEURAL CELL ADHESION MOLECULE 1 (NCAM-1) IS ASSOCIATED TO LONG-TERM AVERSIVE MEMORY IN NEMATODES AND HUMANS

Abstract

Background The Neural Cell Adhesion Molecule 1 (NCAM-1) has been implicated in several brain-related biological processes, including neuronal migration, axonal branching, fasciculation, and synaptogenesis, with a pivotal role in synaptic plasticity. Here, using an interdisciplinary approach we investigated the evolutionary conserved role of Neural Cell Adhesion Molecule 1 (NCAM-1) in learning and memory. Methods First, we examined the temporal transcriptome profiles during C. elegans aversive olfactory long-term memory in a large-scale gene expression study (up to 24 hours upon conditioning). We observed sustained changes in NCAM-1 expression and thus we further investigated its association with aversive memory by using molecular genetics methods. Following, we examined the link between molecular signatures of the NCAM-1 gene and aversive memory in two independent human samples of European descent, by using genome-wide expression and methylation profiling. Finally, in a population of genocide survivors of African descent we investigated the link between NCAM-1 promoter DNA methylation and PTSD. Results NCAM-1 expression showed sustained expression changes up to 24 hours upon aversive olfactory conditioning. Loss of NCAM-1 function selectively impaired long-term memory in a negative but not in positive olfactory associative memory paradigm, without causing acquisition, sensory, motor or short-term memory deficits. Finally, both C. elegans and human NCAM-1 expression in nematodes rescued loss of C. elegans NCAM-1 gene function. Considering the conserved role of NCAM-1 in higher complex organisms, we next expanded our C. elegans findings in human. In two samples of European descent, we showed a negative correlation between DNA methylation of the NCAM-1 promoter and aversive memory (i.e., recognition of negative pictures) as well as a strong positive correlation between NCAM-1 expression and the same recognition performance. In the second sample, we could also show a strong correlation between NCAM-1 expression and long-delayed recall of negative pictures. Finally, in a population of genocide survivors DNA methylation at NCAM-1 gene promoter was inversely correlated with intrusive memories symptoms and Posttraumatic Stress Disorder (PTSD) risk. Discussion Taken together, our results support a conserved role of NCAM-1 in negative associative memory from nematodes to humans and might, ultimately, prove to be helpful in elucidating diagnostic markers and suggest novel therapy targets for memory-related disorders, like PTSD.