Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-08, Vol.108 (33), p.13764-13769
• Main Authors: Etherton, Mark, Földy, Csaba, Sharma, Manu, Tabuchi, Katsuhiko, Liu, Xinran, Shamloo, Mehrdad, Malenka, Robert C, Südhof, Thomas C
• Format: Article
• Language: English
• Subjects: alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; Animals; Autism; Autistic disorder; Autistic Disorder - genetics; Biological Sciences; Brain; cell adhesion; Cell adhesion molecules; Cell Adhesion Molecules, Neuronal - genetics; Cerebral Cortex - physiology; cortex; Cortex (somatosensory); Dendritic branching; gene expression regulation; Genes; Genetic mutation; Glutamic acid receptors (ionotropic); Hippocampus; Hippocampus - physiology; humans; Kinetics; light microscopy; Long term potentiation; Long-Term Potentiation - genetics; Maze learning; Membrane Proteins - genetics; Mice; Mice, Mutant Strains; mutants; Mutation; Mutation, Missense - physiology; N methyl D aspartate receptors; N-Methyl-D-aspartic acid receptors; Nerve Tissue Proteins - genetics; Neurons; patients; phenotype; Phenotypes; Point mutation; receptors; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Rodents; Social behavior; Social interaction; Social interactions; stratum radiatum; synapse; Synapses; Synapses - genetics; Synapses - physiology; Synaptic transmission; Synaptic Transmission - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1111093108

Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3R451C knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3R451C mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3R451C mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3R451C mutation caused an ∼1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3R451C mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3R451C mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner.