Loss of the zinc receptor ZnR/GPR39 in mice enhances anxiety-related behavior and motor deficits, and modulates KCC2 expression in the amygdala

Background: Mood disorders, particularly depression and anxiety, are associated with zinc dyshomeostasis and aberrant GABAergic signaling. Activation of ZnR/GPR39 by synaptic zinc in the hippocampus triggers phosphorylation of extracellular regulated kinase (ERK1/2), which regulates the K⁺/Cl⁻ cotransporter (KCC2) and thereby GABAergic inhibitory neurotransmission and seizure activity. Therefore, we studied whether impaired ZnR/GPR39 signaling is linked to anxiety-related behavior in male or female mice. Results: Using the acoustic startle response, elevated plus maze, and open field test, we found increased anxiety-related behavior in ZnR/GPR39 knockout (KO) mice. Despite a well-established sex difference, where females are typically more prone to anxiety, both male and female ZnR/GPR39 KO mice exhibited increased anxiety-related behavior compared to wildtype (WT) mice. Additionally, ZnR/GPR39 KO mice displayed impaired motor coordination in the pole and rotarod tests but did not show reduced muscle strength, as indicated by a grip test. Finally, we found intrinsic alterations in the expression level of KCC2, a major Cl⁻ transporter regulating GABAergic signaling, in the amygdala of naïve ZnR/GPR39 KO mice compared to controls. Conclusions: Our findings indicate that loss of ZnR/GPR39 enhances anxiety-related behavior in both male and female mice. Moreover, ZnR/GPR39 KO mice exhibit impaired motor coordination, which may be associated with increased anxiety. Finally, we demonstrate that loss of ZnR/GPR39 modulates the expression of KCC2 in the amygdala. Thus, we propose that ZnR/GPR39 can serve as a target for regulating GABAergic signaling in anxiety treatment.