|An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus.
|Year of Publication
|Etherton MR, Tabuchi K, Sharma M, Ko J, Südhof TC
|2011 Jun 03
|Amino Acid Sequence, Amino Acid Substitution, Animals, Autistic Disorder, Carrier Proteins, Cell Adhesion Molecules, Neuronal, Cells, Cultured, Cercopithecus aethiops, COS Cells, Cytoplasm, Electrophysiology, Female, Hippocampus, Humans, Male, Membrane Proteins, Mice, Mice, Knockout, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Point Mutation, Receptors, AMPA, Recombination, Genetic, Sequence Homology, Amino Acid, Synapses, Synaptic Transmission
Neuroligins are evolutionarily conserved postsynaptic cell-adhesion molecules that function, at least in part, by forming trans-synaptic complexes with presynaptic neurexins. Different neuroligin isoforms perform diverse functions and exhibit distinct intracellular localizations, but contain similar cytoplasmic sequences whose role remains largely unknown. Here, we analysed the effect of a single amino-acid substitution (R704C) that targets a conserved arginine residue in the cytoplasmic sequence of all neuroligins, and that was associated with autism in neuroligin-4. We introduced the R704C mutation into mouse neuroligin-3 by homologous recombination, and examined its effect on synapses in vitro and in vivo. Electrophysiological and morphological studies revealed that the neuroligin-3 R704C mutation did not significantly alter synapse formation, but dramatically impaired synapse function. Specifically, the R704C mutation caused a major and selective decrease in AMPA receptor-mediated synaptic transmission in pyramidal neurons of the hippocampus, without similarly changing NMDA or GABA receptor-mediated synaptic transmission, and without detectably altering presynaptic neurotransmitter release. Our results suggest that the cytoplasmic tail of neuroligin-3 has a central role in synaptic transmission by modulating the recruitment of AMPA receptors to postsynaptic sites at excitatory synapses.
|PubMed Central ID
|R37 MH052804 / MH / NIMH NIH HHS / United States