Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation
Neuroligin-2 (Nlgn2) is a key synaptic adhesion protein at virtually all GABAergic synapses, which recruits GABA<sub>A</sub>Rs by promoting assembly of the postsynaptic gephyrin scaffold. Intriguingly, loss of Nlgn2 differentially affects subsets of GABAergic synapses, indicating that synapse-specific interactors and redundancies define its function, but the nature of these interactions remain poorly understood. Here we investigated how Nlgn2 function in hippocampal area CA1 is modulated by two proposed interaction partners, MDGA1 and MDGA2. We show that loss of MDGA1 expression, but not heterozygous deletion of MDGA2, ameliorates the abnormal cytosolic gephyrin aggregation, the reduction in inhibitory synaptic transmission and the exacerbated anxiety-related behaviour characterizing Nlgn2 knockout (KO) mice. Additionally, combined Nlgn2 and MDGA1 deletion causes an exacerbated layer-specific loss of gephyrin puncta. Given that both Nlgn2 and the MDGA1 have been correlated with many psychiatric disorders, our data support the notion that cytosolic gephyrin aggregation may represent an interesting target for novel therapeutic strategies.
Authors
- Janetti Signorelli (ORCID: https://orcid.org/0000-0001-9776-2690)
- Jens Wiltfang (ORCID: https://orcid.org/0000-0003-1492-5330)
- Erinn Gideons (ORCID: https://orcid.org/0000-0003-4778-3869)
- Tommaso Zeppillo
- Heba Ali (ORCID: https://orcid.org/0000-0003-2833-8735)
- Sally Wenger
- Dilja Krueger‐Burg (ORCID: https://orcid.org/0000-0001-5597-6287)
- Francisco José López-Murcia (ORCID: https://orcid.org/0000-0002-0778-4106)
- Sowbarnika Ravichandran (ORCID: https://orcid.org/0000-0001-7150-3009)
- Holger Taschenberger (ORCID: https://orcid.org/0000-0003-3186-3231)
- JeongSeop Rhee (ORCID: https://orcid.org/0000-0002-8560-3630)
- Tamara C. Ritter (ORCID: https://orcid.org/0000-0003-1821-0316)
- Nils Brose (ORCID: https://orcid.org/0000-0003-0938-8534)
- Michael J. Schmeißer (ORCID: https://orcid.org/0000-0002-5514-1922)
Institutions
- Universidad de Antofagasta (CL)
- Johannes Gutenberg University Mainz (DE)
- German Center for Neurodegenerative Diseases (DE)
- Bellvitge University Hospital (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Max Planck Institute of Experimental Medicine (DE)
- University of Aveiro (PT)
- University of Göttingen (DE)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-09-17
- DOI
- https://doi.org/10.1038/s42003-024-06789-z
- Citations
- 7
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 1.88
Funders
- Deutsche Forschungsgemeinschaft
- Volkswagen Foundation
- Bundesministerium für Bildung und Forschung
- Ministerio de Educación, Gobierno de Chile
- Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und Molekulare Biowissenschaften