Neural Cell Adhesion Molecule-Associated Polysialic Acid Regulates Synaptic Plasticity and Learning by Restraining the Signaling through GluN2B-Containing NMDA Receptors

Abstract

The neural cell adhesion molecule (NCAM) is the predominant carrier of α2,8 polysialic acid (PSA) in the mammalian brain. Abnormalities in PSA and NCAM expression are associated with schizophrenia in humans and cause deficits in hippocampal synaptic plasticity and contextual fear conditioning in mice. Here, we show that PSA inhibits opening of recombinant NMDA receptors composed of GluN1/2B (NR1/NR2B) or GluN1/2A/2B (NR1/NR2A/NR2B) but not of GluN1/2A (NR1/NR2A) subunits. Deficits in NCAM/PSA increase GluN2B-mediated transmission and Ca2+ transients in the CA1 region of the hippocampus. In line with elevation of GluN2B-mediated transmission, defects in long-term potentiation in the CA1 region and contextual fear memory in NCAM/PSA-deficient mice are abrogated by application of a GluN2B-selective antagonist. Furthermore, treatment with the glutamate scavenger glutamic-pyruvic transaminase, ablation of Ras-GRF1 (a mediator of GluN2B signaling to p38 MAPK), or direct inhibition of hyperactive p38 MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38 MAPK signaling pathway. These findings implicate carbohydrates carried by adhesion molecules in modulating NMDA receptor signaling in the brain and demonstrate reversibility of cognitive deficits associated with ablation of a schizophrenia-related adhesion molecule.

Identification of gene ontologies linked to prefrontal–hippocampal functional coupling in the human brain

“…NRCAM-PSA-expressing interneurons in mice show reduced dendritic spine numbers, decreased arborization, and changes in the synaptic connectivity (54). A study of cultured hippocampal neurons showed that PSA-NRCAM is required for N-methyl-D-aspartate (NMDA) receptor-dependent LTP and acts as an antagonist at N2RB-subunit-bearing NMDA receptors, preventing glutamate-induced cell death (55,56). The role of NRCAM at NMDA receptors is of particular interest given that NMDA receptor hypofunction in the prefrontal cortex is one of the leading schizophrenia hypotheses and has been linked to the cognitive symptoms and oscillatory disturbances associated with the disease (57).…”

Restoration of Synaptic Plasticity and Learning in Young and Aged NCAM-Deficient Mice by Enhancing Neurotransmission Mediated by GluN2A-Containing NMDA Receptors

“…Recent studies have revealed the importance of GluN modulation by cell adhesion molecules such as the neural cell adhesion molecule (NCAM) (Hammond et al, 2006;Kochlamazashvili et al, 2010). NCAM, which belongs to the Ig superfamily of cell adhesion molecules, is involved in diverse functions during neurodevelopment (Maness and Schachner, 2007), and it is func-tionally modified by long homopolymers of ␣2,8-linked sialic acid residues known as polysialic acid (PSA) (Rutishauser, 2008).…”

Polysialylation of the Neural Cell Adhesion Molecule: Setting the Stage for Plasticity Across Scales of Biological Organization

“…Polysialylation of NCAM has also been shown to regulate neuritogenesis (Seidenfaden, 2006), and axonal growth (Doherty et al, 1990;Zhang et al, 1992) synaptic plasticity and activity-dependent cell remodeling, which has been extensively reviewed (Bonfanti & Theodosis, 2009;Muller et al, 2010;Kochlamazashvili et al, 2010). The effects of PSA-NCAM on axonal fasciculation and defasciculation in different systems have been reported and seem to depend on a combination of both intrinsic and context/environment dependent effects (reviewed by Durbec & Cremer, 2001).…”