Upregulation of Polysialylated Neural Cell Adhesion Molecule in the Dorsal Hippocampus after Contextual Fear Conditioning Is Involved in Long-Term Memory Formation

Abstract

The role of the hippocampus in pavlovian fear conditioning is controversial. Although lesion and pharmacological inactivation studies have suggested a key role for the dorsal hippocampus in contextual fear conditioning, the involvement of the ventral part is still uncertain. Likewise, the debate is open with regard to the putative implication of each hippocampal subdivision in fear conditioning to a discrete conditioned stimulus. We explored the potential existence of dissociations occurring in the dorsal versus ventral hippocampus at the cellular level while dealing with either contextual or cued fear conditioning and focused in a molecular "signature" linked to structural plasticity, the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). We found an upregulation of PSA-NCAM expression in the dorsal (but not ventral) dentate gyrus at 24 h after contextual (but not tone) fear conditioning. Specific removal of PSA through microinfusion of the enzyme endoneuraminidase-N in the dorsal (but not ventral) hippocampus reduced freezing responses to the conditioned context. Therefore, we present evidence for a specific role of PSA-NCAM in the dorsal hippocampus in the plasticity processes occurring during consolidation of the context representation after "standard" contextual fear conditioning. Interestingly, we also found that exposing animals just to the context induced an activation of PSA-NCAM in both dorsal and ventral dentate gyrus. Altogether, these findings highlighting the distinctive occurrence of these neuroplastic processes in the dorsal hippocampus during the standard contextual fear-conditioning task enlighten the ongoing debate about the involvement of these hippocampal subdivisions in pavlovian fear conditioning.

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.…”

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]). …”

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].…”