Neuroligin 1 is dynamically exchanged at postsynaptic sites.
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.
Schapitz
Inga U
IU
Center for Molecular Neurobiology (ZMNH), University of Hamburg Medical School, D-20251 Hamburg, Germany.
Behrend
Bardo
B
Pechmann
Yvonne
Y
Lappe-Siefke
Corinna
C
Kneussel
Silas J
SJ
Wallace
Karen E
KE
Stempel
A Vanessa
AV
Buck
Fritz
F
Grant
Seth G N
SG
Schweizer
Michaela
M
Schmitz
Dietmar
D
Schwarz
Jürgen R
JR
Holzbaur
Erika L F
EL
Kneussel
Matthias
M
D000818:Animals; D019921:Biotinylation; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D004398:Dyneins / Q000378:metabolism; D004594:Electrophysiology; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017774:Long-Term Potentiation / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000502:physiology; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D014162:Transfection
D015816:Cell Adhesion Molecules, Neuronal; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C093438:neuroligin 1; D051528:Guanylate Kinases; D004398:Dyneins