Brain-derived neurotrophic factor restores long-term potentiation in polysialic acid-neural cell adhesion molecule-deficient hippocampus

Abstract

The neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) contribute to long-term potentiation (LTP) in the CA1 hippocampus. Here we report that the deficient LTP found in slices prepared from NCAM knockout mice and in organotypic slice cultures treated with Endo-N, an enzyme that cleaves the PSA moiety of NCAM, can be rescued by brain-derived neurotrophic factor (BDNF). This effect is not reproduced by nerve growth factor, but can be obtained with high concentrations of NT4/5. The effect of BDNF cannot be accounted for by modifications of N-methyl-D-aspartate receptor-dependent responses or of high-frequency bursts. PSA-NCAM, however, could directly interact with BDNF. Exogenous application of PSA residues or recombinant PSA-NCAM also prevents LTP. Furthermore trkB phosphorylation, and thus BDNF signaling, is reduced in both NCAM knockout mice and Endo-N-treated slice cultures. These results suggest that one action of PSA-NCAM could be to sensitize pyramidal neurons to BDNF, thereby modulating activity-dependent synaptic plasticity

Polysialylated Neural Cell Adhesion Molecule Is Involved in Induction of Long-Term Potentiation and Memory Acquisition and Consolidation in a Fear-Conditioning Paradigm

“…Application of PSA (100 g/ml) to slices of NCAMϩ/ϩ mice decreased levels of LTP measured 30 min after the first and second TBS (Fig. 1 D), in agreement with data of Muller et al (2000). Application of the same concentration of PSA to slices of NCAMϪ/Ϫ hippocampi significantly increased LTP as compared with the control site and reached levels comparable with those measured in NCAMϩ/ϩ hippocampi (Fig.…”

“…These effects of PSA and PSA-NCAM-Fc could be explained by different mechanisms. For instance, excess of PSA has been shown to interfere with induction of LTP (Muller et al, 2000; present study) and brain-derived neurotrophic factor signaling (Muller et al, 2000). PSA and PSA-NCAM-Fc may also function as competitive antagonists abolishing PSA-NCAMdriven synaptogenesis at postsynaptic sites at which PSA-NCAM expression is upregulated by a learning event (Fox et al, 1995;Murphy et al, 1996;O'Connell et al, 1997;Sandi et al, 2003).…”

“…Perturbation of NCAM functions by ablation of NCAM or by disruption of NCAM-mediated interactions in vitro and in vivo impaired synaptic plasticity in the hippocampus, induced amnesia in a passive avoidance task, and caused spatial memory deficits (Doyle et al, 1992;Cremer et al, 1994Cremer et al, , 1998Luthi et al, 1994;Arami et al, 1996;Muller et al, 1996Muller et al, , 2000Bukalo et al, 2004;Stoenica et al, 2006). NCAM can carry in its fifth immunoglobulin-like domain long chains of sialic acid residues in an unusual ␣-2,8 linkage, forming a large negatively charged and hydrated glycan shell, called polysialic acid (PSA).…”

Polysialyltransferase expression is linked to neuronal migration in the developing and adult zebrafish

“…In addition, PSAbearing NCAM regulates the expression of the low-affinity neurotrophin receptor p75 and thereby promotes survival of these migrating neuronal progenitors (Gascon et al, 2007). PSA attached to NCAM has also been involved in binding and presenting growth factors thereby regulating long-term potentiation (Becker et al, 1996;Muller et al, 2000). Therefore, reversible PSA attachment and removal is crucial for modulating NCAM-activity and, thus, CNS development and function.…”

Polysialic Acid Profiles of Mice Expressing Variant Allelic Combinations of the Polysialyltransferases ST8SiaII and ST8SiaIV

“…In addition to its function as a negative regulator of cell adhesion, polySia was shown to bind heparan sulfate proteoglycans (6), forming a complex that supports synaptogenesis and activity-dependent remodeling of synapses (7). In addition, polySia can bind brain-derived neurotrophic factor to enhance brain-derived neurotrophic factor-dependent survival of cortical neurons (8,9) and appears to be involved in the regulation of neurotransmitter receptor activity (10). Whereas polySia levels are high during embryonic development, expression in the adult is restricted to brain areas of persistent neurogenesis and synaptic plasticity (11).…”