Distinctive PSA-NCAM and NCAM hallmarks in glutamate-induced dendritic atrophy and synaptic disassembly.

María Fernanda Podestá,Analía Reinés,David Colman,Patricia Yam,Nonthué Alejandra Uccelli,Martín Gabriel Codagnone

doi:10.1371/journal.pone.0108921

Abstract

Dendritic and synapse remodeling are forms of structural plasticity that play a critical role in normal hippocampal function. Neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) participate in neurite outgrowth and synapse formation and plasticity. However, it remains unclear whether they contribute to dendritic retraction and synaptic disassembly. Cultured hippocampal neurons exposed to glutamate (5 µM) showed a reduced MAP-2 (+) area in the absence of neuronal death 24 h after the insult. Concomitantly, synapse loss, revealed by decreased synaptophysin and post-synaptic density-95 cluster number and area, together with changes in NCAM and PSA-NCAM levels were found. Dendritic atrophy and PSA-NCAM reduction proved NMDA-receptor dependent. Live-imaging experiments evidenced dendritic atrophy 4 h after the insult; this effect was preceded by smaller NCAM clusters (1 h) and decreased surface and total PSA-NCAM levels (3 h). Simultaneously, total NCAM cluster number and area remained unchanged. The subsequent synapse disassembly (6 h) was accompanied by reductions in total NCAM cluster number and area. A PSA mimetic peptide prevented both the dendritic atrophy and the subsequent synaptic changes (6 h) but had no effect on the earliest synaptic remodeling (3 h). Thus, NCAM-synaptic reorganization and PSA-NCAM level decrease precede glutamate-induced dendritic atrophy, whereas the NCAM level reduction is a delayed event related to synapse loss. Consequently, distinctive stages in PSA-NCAM/NCAM balance seem to accompany glutamate-induced dendritic atrophy and synapse loss.

Highlights

IntroductionDendritic and synaptic remodeling in the Cornus Ammonis (CA) 1 and 3 regions, as well as neurogenesis in the Dentate Gyrus (DG) are the mechanisms involved in hippocampal structure reorganization [1,2]
Structural plasticity plays a crucial role in normal hippocampal function
We studied the temporal course of events related to synaptic remodeling and dendritic retraction by evaluating the expression pattern of the pre-synaptic marker synaptophysin (SYN), the post-synaptic marker post-synaptic density 95 (PSD95), and the cell adhesion molecules Neural cell adhesion molecule (NCAM) and polysialic acid (PSA)-NCAM

Summary

Introduction

Dendritic and synaptic remodeling in the Cornus Ammonis (CA) 1 and 3 regions, as well as neurogenesis in the Dentate Gyrus (DG) are the mechanisms involved in hippocampal structure reorganization [1,2]. These neuroplastic phenomena enable hippocampal neurons to modify their synaptic morphology, which in turn allows them to adapt to new situations or environmental changes. Whether structural remodeling should be prevented or promoted in the aforementioned pathologies remains a matter of debate, since it may serve to prevent further damage In this regard, alterations in somatodendritic, axonal and synaptic components have been proposed as putative mechanisms underlying hippocampal shrinkage [7]. Dendritic atrophy and synapse loss have been demonstrated in a number of the above mentioned disorders [8]

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