Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development

• Published in: Neuron (Cambridge, Mass.) Vol. 96; no. 4; pp. 808 - 826.e8
• Main Authors: Li, Jun, Han, Wenyan, Pelkey, Kenneth A., Duan, Jingjing, Mao, Xia, Wang, Ya-Xian, Craig, Michael T., Dong, Lijin, Petralia, Ronald S., McBain, Chris J., Lu, Wei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-11-2017; Elsevier Limited
• Subjects: Animals; Cell adhesion; Cell adhesion & migration; cell adhesion molecule; Cell adhesion molecules; Cell Adhesion Molecules, Neuronal - physiology; Cells, Cultured; collybistin; development; Dissection; GABA; GABAergic Neurons - physiology; GABAergic synapse; gamma oscillation; gephyrin; Hippocampus; Hippocampus - growth & development; Hippocampus - physiology; Interneurons; Membrane Proteins - physiology; Mice, Knockout; Nerve Tissue Proteins - physiology; Neural Inhibition - physiology; Neurogenesis - physiology; Neuroligin 2; Neurons; Phosphatase; Proteins; Rodents; seizure; Seizures - physiopathology; Slitrk3; Synapses; Synapses - physiology; Synaptic Transmission - physiology; Synaptogenesis; γ-Aminobutyric acid; development; GABAergic synapse; seizure; Neuroligin 2; gamma oscillation; GABA; Slitrk3; cell adhesion molecule; gephyrin; collybistin
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2017.10.003

In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. Although numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin 2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reveal how unique postsynaptic CAMs work in concert to control synaptogenesis and establish a general framework for GABAergic synapse development.
•Neuroligin 2 is critical for GABAergic synapse formation in developing neurons•As neurons mature, GABAergic synaptogenesis requires both Neuroligin 2 and Slitrk3•Neuroligin 2 interacts with Slitrk3 to regulate GABAergic synapse development•The Neuroligin 2-Slitrk3 interaction is important for hippocampal network activity
Li et al. report a hierarchical process mediated by Neuroligin 2 and Slitrk3 for GABAergic synapse development. Neuroligin 2 also interacts with Slitrk3 to regulate GABAergic synaptogenesis. Selective perturbation of this interaction decreases GABAergic synaptic transmission and impairs hippocampal network activities.