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 GABAARs by promoting assembly of the postsynaptic gephyrin scaffold. Intriguingly, loss of Nlgn2 differentially affects subsets of GABAergic synapses, indicating that synapse-specific interact...

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Detalles Bibliográficos
Autores: Signorelli, Janetti, Zeppillo, Tommaso, Ali, Heba, Ravichandran, Sowbarnika, Ritter, Tamara C., Wenger, Sally, López Murcia, Francisco José, Gideons, Erinn, Schmeisser, Michael J., Wiltfang, Jens, Rhee, JeongSeop, Brose, Nils, Taschenberger, Holger, Krueger-Burg, Dilja
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/216575
Acceso en línea:https://hdl.handle.net/2445/216575
Access Level:acceso abierto
Palabra clave:Ratolins (Animals de laboratori)
Proteïnes portadores
Hipocamp (Cervell)
Proteïnes de membrana
Mice (Laboratory animals)
Carrier proteins
Hippocampus (Brain)
Membrane proteins
Descripción
Sumario:Neuroligin-2 (Nlgn2) is a key synaptic adhesion protein at virtually all GABAergic synapses, which recruits GABAARs 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.

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