Cadherin activity is required for activity-induced spine remodeling

Abstract

Neural activity induces the remodeling of pre- and postsynaptic membranes, which maintain their apposition through cell adhesion molecules. Among them, N-cadherin is redistributed, undergoes activity-dependent conformational changes, and is required for synaptic plasticity. Here, we show that depolarization induces the enlargement of the width of spine head, and that cadherin activity is essential for this synaptic rearrangement. Dendritic spines visualized with green fluorescent protein in hippocampal neurons showed an expansion by the activation of AMPA receptor, so that the synaptic apposition zone may be expanded. N-cadherin-venus fusion protein laterally dispersed along the expanding spine head. Overexpression of dominant-negative forms of N-cadherin resulted in the abrogation of the spine expansion. Inhibition of actin polymerization with cytochalasin D abolished the spine expansion. Together, our data suggest that cadherin-based adhesion machinery coupled with the actin-cytoskeleton is critical for the remodeling of synaptic apposition zone.

β-Catenin regulates excitatory postsynaptic strength at hippocampal synapses

“…At mature excitatory synapses, where unlike inhibitory synapses, N-cadherin expression persists after synaptogenesis, the cadherincatenin complex has been previously implicated in dendritic spine morphogenesis (24,25,27). In this work, we demonstrated a role for the cadherin-catenin complex in regulating excitatory synaptic strength.…”

“…Accordingly, impairing the adhesive activity of cadherins by deletion of ␤-catenin or N-cadherin reduces the number of reserve pool synaptic vesicles at the presynaptic terminal, resulting in enhanced synaptic depression during repetitive stimulation (21,22). Moreover, overexpressing an N-cadherin mutant lacking the extracellular domain or ␤-catenin mutants with an altered phosphorylation site alters spine morphology and synaptic efficacy (23)(24)(25)(26). Analysis of ␣N-catenin knockout mice has also revealed a requirement for the cadherin link to the actin cytoskeleton in regulating spine dynamics (27).…”

Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice

“…In order to make an objective distinction between spines and filopodia, we calculated the ratio of the width and the length for each protrusion. Protrusions with a ratio above or equal to 0,5 were considered as spines and conversely, protrusions with a ratio below 0.5 were considered as filopodia (Okamura et al, 2004). Averages of protrusion densities of three independent experiments were compared with unpaired two-tailed Student's T-tests.…”

Catenins: playing both sides of the synapse

“…Consistent with this, disruption of cadherin function inhibits synapse formation [11]. Interfering with cadherin function also disrupts postsynaptic spine morphology [11], and cadherins are required for activity-induced spine remodeling [12]. Although these data indicate that cadherins are necessary for synapse development, they do not appear to be sufficient since cadherin-mediated adhesion alone does not induce synapse formation in vitro [13].…”

“…Cadherin function is required for activity-driven spine expansion [12] and, interestingly, activity increases spine localization of both β-catenin and α-N-catenin [16,17]. Adhering to the new model of α-catenin function, increasing levels of the β-catenin-α-N-catenin complex within the spine would cause a raise in α-N-catenin concentration at the synapse, promoting its dimerization.…”