A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation

The neural cell adhesion molecule (NCAM) plays a critical role in development and plasticity of the nervous system and is involved in the mechanisms of learning and memory. Here, we show that intracerebroventricular administration of the FG loop (FGL), a synthetic 15 amino acid peptide corresponding to the binding site of NCAM for the fibroblast growth factor receptor 1 (FGFR1), immediately after training rats in fear conditioning or water maze learning, induced a long-lasting improvement of memory. In primary cultures of hippocampal neurons, FGL enhanced the presynaptic function through activation of FGFR1 and promoted synapse formation. These results provide the first evidence for a memory-facilitating effect resulting from a treatment that mimics NCAM function. They suggest that increased efficacy of synaptic transmission and formation of new synapses probably mediate the cognition-enhancing properties displayed by the peptide.

A key role for nectin-1 in the ventral hippocampus in contextual fear memory

Martina Fantin, Jocelin Grosse, Maria del Carmen Sandi Perez, Michael van der Kooij

Nectins are cell adhesion molecules that are widely expressed in the brain. Nectin expression shows a dynamic spatiotemporal regulation, playing a role in neural migratory processes during development. Nectin-1 and nectin-3 and their heterophilic trans-interactions are important for the proper formation of synapses. In the hippocampus, nectin-1 and nectin-3 localize at puncta adherentia junctions and may play a role in synaptic plasticity, a mechanism essential for memory and learning. We evaluated the potential involvement of nectin-1 and nectin-3 in memory consolidation using an emotional learning paradigm. Rats trained for contextual fear conditioning showed transient nectin-1—but not nectin-3—protein upregulation in synapse-enriched hippocampal fractions at about 2 h posttraining. The upregulation of nectin-1 was found exclusively in the ventral hippocampus and was apparent in the synaptoneurosomal fraction. This upregulation was induced by contextual fear conditioning but not by exposure to context or shock alone. When an antibody against nectin-1, R165, was infused in the ventral-hippocampus immediately after training, contextual fear memory was impaired. However, treatment with the antibody in the dorsal hippocampus had no effect in contextual fear memory formation. Similarly, treatment with the antibody in the ventral hippocampus did not interfere with acoustic memory formation. Further control experiments indicated that the effects of ventral hippocampal infusion of the nectin-1 antibody in contextual fear memory cannot be ascribed to memory non-specific effects such as changes in anxiety-like behavior or locomotor behavior. Therefore, we conclude that nectin-1 recruitment to the perisynaptic environment in the ventral hippocampus plays an important role in the formation of contextual fear memories. Our results suggest that these mechanisms could be involved in the connection of emotional and contextual information processed in the amygdala and dorsal hippocampus, respectively, thus opening new venues for the development of treatments to psychopathological alterations linked to impaired contextualization of emotions.

Public Library of Science2013

Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning

Maria del Carmen Sandi Perez

The neural cell adhesion molecule (NCAM) plays a key role in synaptic plasticity and memory formation. We have recently developed a synthetic peptide, termed C3d, which, through the binding to the first, N-terminal immunoglobulin-like (Ig) module in the extracellular portion of NCAM, has been shown to promote neurite outgrowth and synapse formation in vitro, and to interfere with passive avoidance memory in rats in vivo. In this study, we investigated whether the i.c.v. administration of C3d, either 5.5 h after or 2 days before training, could be effective to modulate the strength at which emotional memory for aversive situations is established into a long-term memory. The effects of the peptide were evaluated in adult male Wistar rats trained in the contextual fear conditioning task. The results indicated that C3d significantly reduced the subsequent long-term retention of the conditioned fear response when administered 5.5 h post-training, as indicated by retention tests performed 2-3 and 7 days post-training. However, this treatment failed to influence conditioning for this task when injected 2 days pre-training. Additional experiments showed that C3d did not influence the emotional or locomotor behaviour of the animals, when tested in the open field task. Furthermore, hippocampal levels of microtubule-associated protein 2 (MAP2), Synaptophysin and NCAM were found unchanged when evaluated by enzyme-linked immunosorbent assay in crude synaptosomal preparations 2 days after peptide i.c.v. injection. Therefore, post-training injection of this synthetic peptide was efficient to attenuate the strength at which memory for contextual fear conditioning was enduringly stored, whilst it did not affect the acquisition of new memories. In addition to further support the view that NCAM is critically involved in memory consolidation, the current findings suggest that the NCAM IgI module is a potential target for the development of therapeutic drugs capable to reduce the cognitive impact induced by exposure to intensive stress experiences.

2003

Selective learning and memory impairments in mice deficient for polysialylated NCAM in adulthood

Kamila Markram, Maria del Carmen Sandi Perez

The neural cell adhesion molecule (NCAM) has been implicated in regulating synaptic plasticity mechanisms as well as memory consolidation processes. Attachment of polysialic acid to NCAM (PSA-NCAM) has been reported to down-regulate its adhesive forces, a process hypothesized to be implicated in synapse selection after learning experiences. PSA-NCAM has been critically implicated in hippocampus-related synaptic plasticity and memory storage, but information about its functional role in other brain areas remains scarce. Here, we studied mice deficient for polysialyltransferase-1 (ST8SialV/PST-1), an enzyme which attaches PSA to NCAM during postnatal development and adulthood, and whose deficiency results in a drastic reduction of PSA-NCAM expression throughout the brain in adulthood. Mice were tested for their performance in the water maze and auditory fear conditioning (AFC). We report that ST8SiaIV knockout mice were impaired in spatial as well as reversal learning in the water maze. On the other hand, AFC was intact and ST8SiaIV mice exhibited no impairments in the acquisition or retention of cued fear memories. Spatial orientation learning and reversal learning require complex integration of spatial information and response selection involving the hippocampus and prefrontal cortex, whereas cued fear conditioning is an associative type of emotional memory that highly depends on amygdala function. Therefore, our results indicate that PSA-NCAM contributes differentially to learning processes that differ in the nature of the neural computations involved, which probably reflects a differential role of this molecule in different brain regions.