Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses

• DOI: 10.1084/jem.20172162
• Publication Date: 2018-05-03T10:30:57Z
• Authors: Bo Zhang; Ozgun Gokce; W. Dylan Hale; Nils Brose; Thomas C. Südhof
• Keywords: Mice, Knockout; Neurons; 0301 basic medicine; 0303 health sciences; Cell Adhesion Molecules, Neuronal; Glycine; Excitatory Postsynaptic Potentials; Synaptic Transmission; 3. Good health; 03 medical and health sciences; Inhibitory Postsynaptic Potentials; Mutation; Synapses; Animals; Autistic Disorder; Research Articles; Brain Stem

In human patients, loss-of-function mutations of the postsynaptic cell-adhesion molecule neuroligin-4 were repeatedly identified as monogenetic causes of autism. In mice, neuroligin-4 deletions caused autism-related behavioral impairments and subtle changes in synaptic transmission, and neuroligin-4 was found, at least in part, at glycinergic synapses. However, low expression levels precluded a comprehensive analysis of neuroligin-4 localization, and overexpression of neuroligin-4 puzzlingly impaired excitatory but not inhibitory synaptic function. As a result, the function of neuroligin-4 remains unclear, as does its relation to other neuroligins. To clarify these issues, we systematically examined the function of neuroligin-4, focusing on excitatory and inhibitory inputs to defined projection neurons of the mouse brainstem as central model synapses. We show that loss of neuroligin-4 causes a profound impairment of glycinergic but not glutamatergic synaptic transmission and a decrease in glycinergic synapse numbers. Thus, neuroligin-4 is essential for the organization and/or maintenance of glycinergic synapses.