Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice

Background The brain levels of glutamate (Glu) and glutamine (Gln) are partially regulated through the Glu–Gln cycle. Astrocytes play a role in regulating the Glu–Gln cycle, and loss of astrocytes has been associated with depressive disorders. We hypothesized that levels of Glu and Gln would be affected by astrocyte loss and dysregulation of the Glu–Gln cycle and that depressive-like behaviours would be closely related to the level of changes in Glu and Gln. Methods We used liquid chromatography to measure Glu and Gln concentrations in the prefrontal cortex of male mice infused with L-α aminoadipic acid (L-AAA), a specific astrocyte toxin, in the prelimbic cortex. Methionine sulfoximine, a Gln synthetase inhibitor, and α-methyl-amino-isobutyric acid, a blocker of neuronal Gln transporters, were used to disturb the Glu–Gln cycle. We assessed the behavioural change by drug infusion using the forced swim test (FST) and sucrose preference test. Results The Glu and Gln levels were decreased on the fifth day after L-AAA infusion, and the infused mice showed longer durations of immobility in the FST and lower sucrose preference, indicative of depressive-like behaviour. Mice in which Gln synthetase or Gln transport were inhibited also exhibited increased immobility in the FST. Direct infusion of L-Gln reversed the increased immobility induced by astrocyte ablation and Glu–Gln cycle impairments. Limitations Genetically modified animal models and diverse behavioural assessments would have been helpful to solidify our conclusions. Conclusion Neuronal Gln deficiency in the pre-frontal cortex may cause depressive behaviours.