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Abstract
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, we investigated the evolutionary conserved role of NCAM-1 in learning and memory. First, we investigated sustained changes in ncam-1 expression following aversive olfactory conditioning in C. elegans using molecular genetic methods. Furthermore, we examined the link between epigenetic signatures of the NCAM1 gene and memory in two human samples of healthy individuals (N = 568 and N = 319) and in two samples of traumatized individuals (N = 350 and N = 463). We found that olfactory conditioning in C. elegans induced ncam-1 expression and that loss of ncam-1 function selectively impaired associative long-term memory, without causing acquisition, sensory, or short-term memory deficits. Reintroduction of the C. elegans or human NCAM1 fully rescued memory impairment, suggesting a conserved role of NCAM1 for memory. In parallel, DNA methylation of the NCAM1 promoter in two independent healthy Swiss cohorts was associated with memory performance. In two independent Sub-Saharan populations of conflict zone survivors who had faced severe trauma, DNA methylation at an alternative promoter of the NCAM1 gene was associated with traumatic memories. Our results support a role of NCAM1 in associative memory in nematodes and humans, and might, ultimately, be helpful in elucidating diagnostic markers or suggest novel therapy targets for memory-related disorders, like PTSD.
Highlights
The fundamental process of memory formation involves several steps ranging from structural and functional remodeling of synapses to changes in gene expression and de novo protein synthesis[1,2,3]
We found that ncam-1 is upregulated at the transcriptional level during a long-term associative memory (LTAM) task in C. elegans. ncam-1 loss of function impaired LTAM, which was fully rescued by introduction of the human NCAM1 in mutant worms, suggesting an evolutionary conserved function of NCAM1 in long-term memory
In order to study the physiological role of the sole C. elegans NCAM1 ortholog, we first generated a deletion in the ncam-1 gene using the CRISPR/Cas[9] system (Supplemental Fig. S1)
Summary
The fundamental process of memory formation involves several steps ranging from structural and functional remodeling of synapses to changes in gene expression and de novo protein synthesis[1,2,3]. It became clear that both remodeling and formation of new synapses, where neuronal cell adhesion molecules play a. The three NCAM1 isoforms differ in their intracellular part and exhibit distinct expression pattern and functions[11]. NCAM1 has been shown to be involved in both short- and long-term synaptic plasticity[4,12,13]. The role of NCAM1 in memory was first proposed by a pioneering study, which demonstrated that administration of antibodies or synthetic peptides against NCAM1 inhibited the induction of LTP14.
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