Open AccessThe γ-Protocadherins Interact Physically and Functionally with Neuroligin-2 to Negatively Regulate Inhibitory Synapse Density and Are Required for Normal Social Interaction
Author(s) -
David M. Steffen,
Sarah L. Ferri,
Charles Marcucci,
Kelsey L. Blocklinger,
Michael J. Molumby,
Ted Abel,
Joshua A. Weiner
Publication year - 2021
Publication title -
molecular neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.569
H-Index - 111
eISSN - 1559-1182
pISSN - 0893-7648
DOI - 10.1007/s12035-020-02263-z
Subject(s) - inhibitory postsynaptic potential , synapse , neuroligin , neuroscience , gephyrin , synaptogenesis , biology , microbiology and biotechnology , genetics , excitatory postsynaptic potential , glycine receptor , glycine , amino acid
Cell adhesion molecules (CAMs) are key players in the formation of neural circuits during development. The γ-protocadherins (γ-Pcdhs), a family of 22 CAMs encoded by the Pcdhg gene cluster, are known to play important roles in dendrite arborization, axon targeting, and synapse development. We showed previously that multiple γ-Pcdhs interact physically with the autism-associated CAM neuroligin-1, and inhibit the latter's ability to promote excitatory synapse maturation. Here, we show that γ-Pcdhs can also interact physically with the related neuroligin-2, and inhibit this CAM's ability to promote inhibitory synapse development. In an artificial synapse assay, γ-Pcdhs co-expressed with neuroligin-2 in non-neuronal cells reduce inhibitory presynaptic maturation in contacting hippocampal axons. Mice lacking the γ-Pcdhs from the forebrain (including the cortex, the hippocampus, and portions of the amygdala) exhibit increased inhibitory synapse density and increased co-localization of neuroligin-2 with inhibitory postsynaptic markers in vivo. These Pcdhg mutants also exhibit defective social affiliation and an anxiety-like phenotype in behavioral assays. Together, these results suggest that γ-Pcdhs negatively regulate neuroligins to limit synapse density in a manner that is important for normal behavior.