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Free keywords:
Animals
Biotinylation
Cell Adhesion Molecules, Neuronal/*metabolism
Cells, Cultured
Cytoskeleton/metabolism
Dendritic Spines/*metabolism
Disks Large Homolog 4 Protein
Dyneins/metabolism
Electrophysiology
Guanylate Kinases
Hippocampus/cytology/*metabolism
Immunohistochemistry
Immunoprecipitation
Intracellular Signaling Peptides and Proteins/metabolism
Long-Term Potentiation/physiology
Long-Term Synaptic Depression/physiology
Mass Spectrometry
Membrane Proteins/metabolism
Mice
Mice, Transgenic
Neurons/metabolism
Synapses/*metabolism
Synaptic Transmission/*physiology
Transfection
Abstract:
Neuroligins are postsynaptic cell adhesion molecules that associate with presynaptic neurexins. Both factors form a transsynaptic connection, mediate signaling across the synapse, specify synaptic functions, and play a role in synapse formation. Neuroligin dysfunction impairs synaptic transmission, disrupts neuronal networks, and is thought to participate in cognitive diseases. Here we report that chemical treatment designed to induce long-term potentiation or long-term depression (LTD) induces neuroligin 1/3 turnover, leading to either increased or decreased surface membrane protein levels, respectively. Despite its structural role at a crucial transsynaptic position, GFP-neuroligin 1 leaves synapses in hippocampal neurons over time with chemical LTD-induced neuroligin internalization depending on an intact microtubule cytoskeleton. Accordingly, neuroligin 1 and its binding partner postsynaptic density protein-95 (PSD-95) associate with components of the dynein motor complex and undergo retrograde cotransport with a dynein subunit. Transgenic depletion of dynein function in mice causes postsynaptic NLG1/3 and PSD-95 enrichment. In parallel, PSD lengths and spine head sizes are significantly increased, a phenotype similar to that observed upon transgenic overexpression of NLG1 (Dahlhaus et al., 2010). Moreover, application of a competitive PSD-95 peptide and neuroligin 1 C-terminal mutagenesis each specifically alter neuroligin 1 surface membrane expression and interfere with its internalization. Our data suggest the concept that synaptic plasticity regulates neuroligin turnover through active cytoskeleton transport.
