Neural Cell Adhesion Molecule-associated Polysialic Acid Potentiates α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Currents

Abstract

The highly negatively charged polysialic acid (PSA) is a carbohydrate predominantly carried by the neural cell adhesion molecule (NCAM) in mammals. NCAM and, in particular, PSA play important roles in cellular and synaptic plasticity. Here we investigated whether PSA modulates the activity of the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors (AMPA-Rs). Single channel recordings of affinity-purified AMPA-Rs reconstituted in lipid bilayers revealed that bacterially derived PSA, called colominic acid, prolonged the open channel time of AMPA-R-mediated currents by severalfold and altered the bursting pattern of the receptor channels but did not modify AMPA-R single channel conductance. This effect was reversible, concentration-dependent, and specific, since monomers of sialic acid and another negatively charged carbohydrate, chondroitin sulfate, did not potentiate single channel AMPA-R currents. Recombinant PSA-NCAM also potentiated currents mediated by reconstituted AMPA-Rs. In pyramidal neurons acutely isolated from the CA1 region of the early postnatal hippocampus, L-glutamate or AMPA (applied in the presence of antagonists blocking voltage-gated Na ؉ and K ؉ currents and N-methyl-D-aspartate and metabotropic glutamate receptors) induced inward currents, which were significantly increased by co-application of colominic acid. Chondroitin sulfate did not affect AMPA-R-mediated currents in CA1 neurons. The effect of colominic acid was age-dependent, since in pyramidal neurons from adult hippocampus, colominic acid failed to potentiate glutamate responses. Thus, our study demonstrates agedependent potentiation of AMPA receptors by PSA via a mechanism probably involving direct PSA-AMPA-R interactions. This mechanism might amplify AMPA-R-mediated signaling in immature cells, thereby affecting their development.

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

“…While the changes reported on NCAM are inhibited by the use of the NMDA receptor antagonist, MK-801 (Schuster et al, 1998), there is some evidence that NMDA receptors can downregulate the expression of PSA-NCAM as observed by Bouzioukh et al (2001) in adult brain stem synapses. The available data from preparation in DG suggest that the changes observed in NCAM180, the major isoform of NCAM, are directly associated with particular NMDA and AMPA receptors subunits such as NR2A and GluR2/3 (Fux et al, 2003) whereas data obtained in cultured CA1 neurons suggest that PSA-NCAM changes may be associated with NMDA NR2B subunit as well as with the AMPA GluR1 subunit (mainly) (Vaithianathan et al, 2004;Hammond et al, 2006). The data we report herein suggest that different mechanisms may be at play in the DG.…”

Functional Role of the Interaction between Polysialic Acid and Myristoylated Alanine-rich C Kinase Substrate at the Plasma Membrane

“…The addition of colominic acid/PSA or of soluble PSA-carrying NCAM to acute hippocampal slices of NCAM-deficient mice restores long term potentiation that is impaired in NCAM-deficient mice, whereas application to the hippocampus of wild-type mice leads to impairment in formation of hippocampus-dependent contextual memory (26). The addition of colominic acid/PSA increased the open time of the AMPA receptors (57,59), whereas colominic acid/PSA addition prevents activation of GluN2B-containing NMDA receptors at low glutamate concentrations (60).…”

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).…”