Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors

Gesche Born, Hannah M. Grayton, Hanna Langhorst, Irina Dudanova, Astrid Rohlmann, Benjamin W. Woodward, David A. Collier, Cathy Fernandes, Markus Missler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)
373 Downloads (Pure)

Abstract

Human genetics has identified rare copy number variations and deleterious mutations for all neurexin genes (NRXN1-3) in patients with neurodevelopmental diseases, and electrophysiological recordings in animal brains have shown that Nrxns are important for synaptic transmission. While several mouse models for Nrxn1a inactivation have previously been studied for behavioral changes, very little information is available for other variants. Here, we validate that mice lacking Nrxn2a exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior, which partially overlap, partially differ from Nrxn1a mutant behaviors. Using patch-clamp recordings in Nrxn2a knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. We also analyse at this cellular level a novel NRXN2 mouse model that carries a combined deletion of Nrxn2a and Nrxn2ß. Electrophysiological analysis of this Nrxn2-mutant mouse shows surprisingly similar defects of excitatory release to Nrxn2a, indicating that the ß-variant of Nrxn2 has no strong function in basic transmission at these synapses. Inhibitory transmission as well as synapse densities and ultrastructure remain unchanged in the neocortex of both models. Furthermore, at Nrxn2a and Nrxn2-mutant excitatory synapses we find an altered facilitation and N-methyl-D-aspartate receptor (NMDAR) function because NMDAR-dependent decay time and NMDAR-mediated responses are reduced. As Nrxn can indirectly be linked to NMDAR via neuroligin and PSD-95, the trans-synaptic nature of this complex may help to explain occurrence of presynaptic and postsynaptic effects. Since excitatory/inhibitory imbalances and impairment of NMDAR function are alledged to have a role in autism and schizophrenia, our results support the idea of a related pathomechanism in these disorders.

Original languageEnglish
Article number3
Number of pages16
JournalFrontiers in Synaptic Neuroscience
Volume7
Issue number0
Early online date19 Feb 2015
DOIs
Publication statusPublished - 19 Feb 2015

Keywords

  • AMPA receptor
  • Anxiety-like behavior
  • Cognition
  • Electron microscopy
  • NMDA receptor
  • Social interaction
  • Synaptic plasticity
  • Vesicle release

Fingerprint

Dive into the research topics of 'Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors'. Together they form a unique fingerprint.

Cite this