Disrupted astrocyte-neuron glutamine-glutamate cycling in the medial prefrontal cortex contributes to depression-like behaviors

The regulation of the homeostasis of the glutamate (Glu)-glutamine (Gln) cycle within the medial prefrontal cortex (mPFC) has garnered substantial interest due to its essential role in maintaining normal emotional behaviors. Chronic stress possesses the potential to disrupt the homeostasis of the Glu-Gln cycle, thereby facilitating the onset of depressive behaviors. Nevertheless, the specific roles of individual components within the Glu-Gln cycle in relation to depression-related behaviors remain incompletely understood. This study aims to elucidate the specific roles of each component by implementing a cell- and region-specific conditional knockout (cKO) strategy. To achieve this goal, the genes encoding glutamine synthetase (GS), glutamate transporter 1 (GLT-1), and sodium-coupled neutral amino acid transporters, SNAT-3 and SNAT-5, were selectively ablated within astrocytes. In addition, the genes encoding SNAT-1 and SNAT-2 were specifically eliminated from glutamatergic neurons. A depressive phenotype was observed in the GS and GLT-1 cKO mice, correlated with increased levels of reactive oxygen/nitrogen species (ROS/RNS) within the mPFC, whereas a reduction in Glu-Gln concentrations was uniquely identified in the GS cKO mice. Conversely, mice with cKO for SNAT-1, SNAT-2, SNAT-3, or SNAT-5 neither exhibited observable depressive-like behaviors nor reduced Glu-Gln levels. However, the simultaneous inactivation of either SNAT-1/SNAT-2 or SNAT-3/SNAT-5 induced depressive-like behaviors and reduced Glu-Gln levels. No systemic stress response or inflammatory manifestations were detected in any of the cKO mice. Furthermore, administration of Gln, acknowledged for its antidepressant properties, to GS cKO mice led to the amelioration of both depressive-like behaviors and Glu-Gln concentrations. These findings elucidate distinct and synergistic roles for the components involved in the Glu-Gln cycle in upholding appropriate Glu-Gln levels and mitigating ROS/RNS within the mPFC. Additionally, our cKO mouse models prove to be valuable tools in researching depression, which may aid in the development of new antidepressant treatments.