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Neuron. 2017 Nov 15;96(4):808-826.e8. doi: 10.1016/j.neuron.2017.10.003. Epub 2017 Oct 26.

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

Author information

1
Synapse and Neural Circuit Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
2
Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
3
Advanced Imaging Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
4
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, University of Exeter, Prince of Wales Road, Exeter EX4 4PS, UK.
5
Genetic Engineering Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
6
Synapse and Neural Circuit Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: luw4@mail.nih.gov.

Abstract

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.

KEYWORDS:

GABA; GABAergic synapse; Neuroligin 2; Slitrk3; cell adhesion molecule; collybistin; development; gamma oscillation; gephyrin; seizure

PMID:
29107521
PMCID:
PMC5957482
DOI:
10.1016/j.neuron.2017.10.003
[Indexed for MEDLINE]
Free PMC Article

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