Dichotomy in the anxiolytic versus antidepressant effect of C-terminal truncation of the GluN2A subunit of NMDA receptors

• NMDA receptors critically influence circuits regulating emotionality.
• The C-terminus of the GluN2A subunit mediates their intracellular signalling.
• GluN2AΔC/ΔC mice showed decreased anxiety, but normal depression-like behaviour.

The glutamate system is thought to play an important role in modulating mood and anxiety. Ionotropic NMDA receptors critically influence neuronal circuits regulating emotional behaviour. Their pharmacological blockade triggers fast antidepressant and anxiolytic effects. In line with this concept, ablation of the GluN2A subunit of NMDA receptors induces antidepressant and anxiolytic effects. However, it is not known if absence of the GluN2A-containing NMDA channel or of the GluN2A-mediated intracellular signalling is responsible for these effects. To further investigate the contribution of the GluN2A-containing NMDA receptors in mood disorders we analysed mice lacking the intracellular C-terminus of the GluN2A subunit (GluN2AΔC/ΔC) in tests relevant for anxiety and depression. Interestingly, GluN2AΔC/ΔC mice showed decreased anxiety, but no anti-depressive-like phenotype, indicating a predominant role of the intracellular signalling of the GluN2A subunit in anxiety. These data suggest distinct roles of the GluN2A subunit as whole vs. its intracellular domain in modulating anxiety and depression-like symptoms and reveal differential molecular targets for the therapy of mood and anxiety disorders.