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

• Published in: Behavioral and brain functions 2024-11, Vol.20 (1), p.31-15, Article 31
• Main Authors: Sagi, Romi, Chakraborty, Moumita, Bogdanovic, Milos, Asraf, Hila, Sekler, Israel, Kofman, Ora, Cohen, Hagit, Hershfinkel, Michal
• Format: Article
• Language: English
• Subjects: Amygdala - metabolism; Animals; Anxiety - genetics; Anxiety - metabolism; Anxiety - psychology; Anxiety-related; Behavior, Animal - physiology; Female; K Cl- Cotransporters; KCC2; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity - physiology; Motor coordination; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Symporters - genetics; Symporters - metabolism; Zinc; Zinc signaling; ZnR/GPR39
• ISSN: 1744-9081; 1744-9081
• DOI: 10.1186/s12993-024-00254-x

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. 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. 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.