ABSTRACT
We show that the loss or inactivation of the polysialic acid (PSA) tail of neural cell adhesion molecule (NCAM) on rat cortical neurons in culture leads to reduced differentiation and survival. The mechanism by which this negative effect is mediated appears to involve the neuronal response to brain-derived neurotrophic factor (BDNF): (i) in the absence of PSA or in the presence of excess free PSA added to the culture medium, BDNF-induced cell signalling is reduced; (ii) the addition of exogenous BDNF to the medium reverses the effect of PSA loss or inactivation. These data suggest that PSA-NCAM, previously shown to modulate cell migration and plasticity, is needed for an adequate sensitivity of neurons to BDNF.
Subject(s)
Brain-Derived Neurotrophic Factor/pharmacology , Cerebral Cortex/cytology , Neural Cell Adhesion Molecule L1 , Neural Cell Adhesion Molecules/metabolism , Neurons/cytology , Sialic Acids/metabolism , Animals , Animals, Newborn , Cell Death/drug effects , Cell Death/physiology , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Survival/drug effects , Cell Survival/physiology , Glycoside Hydrolases/metabolism , Humans , Neural Cell Adhesion Molecules/genetics , Neural Cell Adhesion Molecules/pharmacology , Neurons/metabolism , Rats , Rats, Sprague-Dawley , Receptor, trkB/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Rhabdomyosarcoma , Sialic Acids/genetics , Sialic Acids/pharmacology , Signal Transduction/physiology , Transfection , Tumor Cells, CulturedABSTRACT
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.
