Hippocampal up‐regulation of NCAM expression and polysialylation plays a key role on spatial memory

Abstract

Memory formation has been associated with structural and functional modifications of synapses. Cell adhesion molecules are prominent modulators of synaptic plasticity. Here, we investigated the involvement of the cell adhesion molecules, NCAM, its polysialylated state (PSA-NCAM) and L1 in spatial learning-induced synaptic remodeling and memory storage. A differential regulation of these adhesion molecules was found in the hippocampus of rats submitted to one training session in the spatial, but not cued, version of the Morris water maze. Twenty-four hours after training, synaptic expression of NCAM and PSA-NCAM was increased, whereas L1 appeared markedly decreased. The regulation of these molecules was spatial learning-specific, except for L1 reduction, which could be attributed to swimming under stressful conditions rather than to learning. Subsequent psychopharmacological experiments were performed to address the functional role of NCAM and PSA-NCAM in the formation of spatial memories. Rats received an intracerebroventricular injection of either a synthetic peptide (C3d) aimed to interfere with NCAM function, or endoneuraminidase, an enzyme that cleaves polysialic acid from NCAM. Both treatments affected acquisition of spatial information and lead to impaired spatial memory abilities, supporting a critical role of the observed learning-induced up-regulation of synaptic NCAM expression and polysialylation on spatial learning and memory. Therefore, our findings highlight NCAM as a learningmodulated molecule critically involved in the hippocampal remodeling processes underlying spatial memory formation.

Glucocorticoids act on glutamatergic pathways to affect memory processes

“…In parallel, there was a similar stressful-learning-induced synaptic increase in Ncadherin (a cell-adhesion molecule that interacts with GluA2 subunits and which plays an important role in the formation and growth of dendritic spines [45]). Although this result is purely correlative, it suggests a potential interaction between these two molecules as a mechanism whereby stress can improve memory function (but note that other synaptic cell-adhesion molecules that are also enhanced after stressful learning paradigms could also be involved [46][47][48]). …”

N-methyl-d-aspartate receptor independent changes in expression of polysialic acid-neural cell adhesion molecule despite blockade of homosynaptic long-term potentiation and heterosynaptic long-term depression in the awake freely behaving rat dentate gyrus

“…Although heterosynaptic LTD has recently been shown to require homosynaptic activity (Abraham et al, 2007), we would like to note that the expression of PSA following homosynaptic LTD may differ from our present results in heterosynaptic LTD. In light of the data showing that PSA-NCAM increases in the DG following fear conditioning, odour discrimination or spatial learning (Fox et al, 1995;Foley et al, 2003;Venero et al, 2006;Lopez-Fernandez et al, 2007), and that impairing or promoting PSA-NCAM function accordingly affect learning (Florian et al, 2006;Markram et al, 2007), we raise the question of whether the increase in PSA observed after learning represents another form of plasticity which acts synergistically with LTP or LTD.…”

“…Whereas behavioural studies have found increases in PSA-NCAM in the DG after training (Fox et al, 1995;Foley et al, 2003;Venero et al, 2006;Lopez-Fernandez et al, 2007), no study to date has examined whether LTP or LTD would also produce changes in PSA-NCAM in the DG. Therefore, we sought to examine this issue in vivo in the awake rat.…”

“…Polysialylation of NCAMs has been implicated in hippocampus-dependent memory storage (Fox et al, 1995;Foley et al, 2003;Florian et al, 2006;Venero et al, 2006;Lopez-Fernandez et al, 2007;Markram et al, 2007). Long-term potentiation (LTP) and long-term depression (LTD) are widely accepted models of plasticity involved in memory processes.…”

A small molecule p75NTR ligand protects neurogenesis after traumatic brain injury

“…PSA-NCAM is expressed principally in cells at the subgranular zone (SGZ)-granule cell layer (GCL) interface, representing recently formed and plastic neurons [20,21], with expression also in fibers extending through the GCL into the molecular layer, and a smaller amount on fibers in the hilus. Polysialylation of cell-surface NCAM, which may decrease its homotypic adhesiveness, increases with training [22], and has been implicated in hippocampal memory consolidation in several studies [23][24][25].…”