Journal article
The γ-Protocadherins Interact Physically and Functionally with Neuroligin-2 to Negatively Regulate Inhibitory Synapse Density and Are Required for Normal Social Interaction
Molecular neurobiology, Vol.58(6), pp.2574-2589
01/20/2021
DOI: 10.1007/s12035-020-02263-z
PMCID: PMC8137559
PMID: 33471287
Abstract
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.
Details
- Title: Subtitle
- The γ-Protocadherins Interact Physically and Functionally with Neuroligin-2 to Negatively Regulate Inhibitory Synapse Density and Are Required for Normal Social Interaction
- Creators
- David M Steffen - Department of Biology, The University of Iowa, Iowa City, IA, 52242, USASarah L Ferri - Department of Neuroscience and Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USACharles G Marcucci - Department of Biology, The University of Iowa, Iowa City, IA, 52242, USAKelsey L Blocklinger - Department of Neuroscience and Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USAMichael J Molumby - Department of Biology, The University of Iowa, Iowa City, IA, 52242, USATed Abel - Department of Neuroscience and Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USAJoshua A Weiner - Department of Biology, The University of Iowa, Iowa City, IA, 52242, USA. joshua-weiner@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Molecular neurobiology, Vol.58(6), pp.2574-2589
- DOI
- 10.1007/s12035-020-02263-z
- PMID
- 33471287
- PMCID
- PMC8137559
- NLM abbreviation
- Mol Neurobiol
- ISSN
- 0893-7648
- eISSN
- 1559-1182
- Publisher
- United States
- Grant note
- NS055272 / NINDS NIH HHS K01 MH119540 / NIMH NIH HHS
- Language
- English
- Date published
- 01/20/2021
- Academic Unit
- Liberal Arts and Science Admin; Molecular Physiology and Biophysics; Psychiatry; Stead Family Department of Pediatrics; Psychological and Brain Sciences; Iowa Neuroscience Institute; Biology; Developmental and Behavioral Pediatrics; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984070480502771
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