Role of Neuroligin in Synapse Formation and Autism

Neuroligins mediate synaptogenesis through formation of a trans-synaptic complex with presynaptic neurexins. Interaction of neuroligin 1 with neurexins is regulated by alternative splicing of both neuroligin 1 (at splice site B) and of neurexins (at splice site #4). Full-length neuroligin 1 that binds only beta -neurexin more potently promotes synapse formation in hippocampal neurons, whereas neuroligin 1 lacking splice site B, which binds both alpha - and beta -neurexins, is more efficient at synapse expansion. Mutations in two surface loops of neuroligin 1 abolished neuroligin binding to neurexin 1beta and blocked synapse formation. Neuroligin mutation found in autism spectrum disorders impairs cell-surface transport but does not completely abolish synaptogenic activity. In hippocampal neurons, overexpressed neuroligin 1 enhances excitatory but not inhibitory synaptic responses, and increases the ratio of NMDA to AMPA receptor-mediated synaptic currents. In contrast, genetic deletion of neuroligin 1 in mice decreases NMDA receptor-mediated synaptic currents and the NMDA/AMPA receptor ratio. Contrary to neuroligin 1, neuroligin 2 potentiates inhibitory but not excitatory synaptic responses. The synaptic actions of neuroligin 1 are suppressed by chronic blockade of NMDA receptors or of CaM-kinase II. Neuroligin 1 with an autistic-spectrum syndrome mutation decreases excitatory synaptic responses, consistent with a role for endogenous neuroligin 1 in synapse development. Taken together, our data suggest that neuroligin-neurexin interaction regulated by their alternative splicing promotes formation of specific synapses; synaptogenic function of neuroligin is regulated by NMDA receptor and Cam-kinase II activation, suggesting a critical role for neuroligins in synaptic plasticity and modulation of neural circuits.

Author dc:creator

• Chubykin, Alexander Anatoly

Contributors dc:contributor

• Südhof, Thomas C.

• Embryology
• Synapses
• Autism
• Nerve Tissue Proteins

Language dc:language

en

Identifier

71202774

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/606