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

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

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J Psychiatry Neurosci 2013; 38(3): 183-191

Younghyurk Lee, PhD; Hyeonwi Son, BS; Gyeongwha Kim, MS; Sujeong Kim, BS; Dong Hoon Lee, MD, PhD; Gu Seob Roh, MD, PhD; Sang Soo Kang, PhD; Gyeong Jae Cho, MD, PhD; Wan Sung Choi, PhD; Hyun Joon Kim, PhD

Centre for Addiction and Mental Health, Departments of Pharmacology and Toxicology and Psychiatry, University of Toronto, Toronto, Ont., Canada


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 prefrontal cortex may cause depressive behaviours.

Submitted Feb. 7, 2012; Revised Feb. 23, May 29, July 9, 2012; Accepted July 22, 2012.

Acknowledgement: This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2011-0006200).

Competing interests: H.J. Kim declares having received grant funding for this work as above. None declared for the other authors.

Contributors: S.S. Kang, G.J. Cho, W.S. Choi and H.J. Kim designed the study. Y. Lee acquired and analyzed the data. H. Son, G. Kim and S.J. Kim also acquired the data. D.H. Lee, G.S. Roh and H.J. Kim also analyzed the data. Y. Lee, S.S. Kang and H.J. Kim wrote the article, which all other authors reviewed. All authors approved the final version for publication.

DOI: 10.1503/jpn.120024

Correspondence to: Hyun Joon Kim, Department of Anatomy and Neurobiology, Institute of Health Sciences, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University, 816 Beongil 15, Jinju-daero, Jinju, 660-290, Republic of Korea;