Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Jan 21;25(2):1302.
doi: 10.3390/ijms25021302.

The Role of Glutamine Homeostasis in Emotional and Cognitive Functions

Ji Hyeong Baek  1 , Hyeongchan Park  1 , Hyeju Kang  1 , Rankyung Kim  1 , Jae Soon Kang  1 , Hyun Joon Kim  1
Affiliations
Review

The Role of Glutamine Homeostasis in Emotional and Cognitive Functions

Ji Hyeong Baek et al. Int J Mol Sci. .

Abstract

Glutamine (Gln), a non-essential amino acid, is synthesized de novo by glutamine synthetase (GS) in various organs. In the brain, GS is exclusively expressed in astrocytes under normal physiological conditions, producing Gln that takes part in glutamatergic neurotransmission through the glutamate (Glu)-Gln cycle. Because the Glu-Gln cycle and glutamatergic neurotransmission play a pivotal role in normal brain activity, maintaining Gln homeostasis in the brain is crucial. Recent findings indicated that a neuronal Gln deficiency in the medial prefrontal cortex in rodents led to depressive behaviors and mild cognitive impairment along with lower glutamatergic neurotransmission. In addition, exogenous Gln supplementation has been tested for its ability to overcome neuronal Gln deficiency and reverse abnormal behaviors induced by chronic immobilization stress (CIS). Although evidence is accumulating as to how Gln supplementation contributes to normalizing glutamatergic neurotransmission and the Glu-Gln cycle, there are few reviews on this. In this review, we summarize recent evidence demonstrating that Gln supplementation ameliorates CIS-induced deleterious changes, including an imbalance of the Glu-Gln cycle, suggesting that Gln homeostasis is important for emotional and cognitive functions. This is the first review of detailed mechanistic studies on the effects of Gln supplementation on emotional and cognitive functions.

Keywords: cognitive impairment; depressive disorder; glutamatergic neurotransmission; glutamine.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
The glutamate–glutamine (Glu–Gln) cycle. High-affinity excitatory amino acid transporters (EAATs) in astrocytes, particularly EAAT2, clear Glu from the synaptic cleft. Astrocytes then convert Glu into Gln through glutamine synthetase (GS). Gln is released from astrocytes through sodium-coupled neutral amino acid transporter (SNAT)3 and SNAT5 and taken up by neurons through SNAT1 and SNAT2, where it is converted back to Glu by phosphate-activated glutaminase (PAG). This regenerated Glu is packaged into synaptic vesicles by vesicular glutamate transporters (VGLUTs) and released into synaptic cleft for subsequent excitatory neurotransmission. NMDAR, N-methyl-D-aspartate receptor; AMPAR, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor; KAR, kainite receptor; mGluR, metabotropic glutamate receptor.
Figure 2
Figure 2
Glutamine (Gln) is essential for the homeostasis of glutamatergic neurotransmission. Changes in glutamate–Gln levels and decreased glutamatergic neurotransmission in the prefrontal cortex are commonly found in various animal models of emotional and cognitive disorders of different causes. These changes are reversed by Gln supplementation or direct infusion into the prelimbic cortex, suggesting that maintenance of Gln homeostasis and glutamatergic neurotransmission is important for emotional and cognitive function. L-AAA, L-α aminoadipic acid; MSO, methionine sulfoximine; MeAIB, α-methyl-amino-isobutyric acid.
Figure 3
Figure 3
Glutamine (Gln) supplementation has antidepressive and cognition-improvement effects by protecting the homeostasis of glutamatergic neurotransmission. In a chronic immobilization stress (CIS)-induced depression and cognitive impairment mouse model, reduced glutamatergic neurotransmission was observed in the prefrontal cortex (PFC) along with low glutamate (Glu)—Gln levels, decreased Gln synthetase (GS) activity, and decreased expression levels of the Glu transporter excitatory amino acid transporter 2 (EAAT2) and Gln transporters in neurons (sodium-coupled neutral amino acid transporter [SNAT]1 and SNAT2) and in astrocytes (SNAT3 and SNAT5). Oxidative stress and pro-inflammatory changes were also observed in CIS mice. CIS also induces an increase in the levels of reactive oxygen/nitrogen species (ROS/RNS) and proteins related to ROS/RNS production in the PFC. These deleterious changes caused by chronic stress are reversed to normal levels by Gln supplementation, providing evidence that the restoration of Gln homeostasis through Gln supplementation has antidepressive and cognition-improvement effects. iNOS, inducible nitric oxide synthase; NOX, NADPH oxidase.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Albrecht J., Sidoryk-Wegrzynowicz M., Zielinska M., Aschner M. Roles of glutamine in neurotransmission. Neuron Glia Biol. 2010;6:263–276. doi: 10.1017/S1740925X11000093. - DOI - PubMed
    1. Watford M. Glutamine and glutamate: Nonessential or essential amino acids? Anim. Nutr. 2015;1:119–122. doi: 10.1016/j.aninu.2015.08.008. - DOI - PMC - PubMed
    1. Fernández-Montoya J., Avendaño C., Negredo P. The glutamatergic system in primary somatosensory neurons and its involvement in sensory input-dependent plasticity. Int. J. Mol. Sci. 2017;19:69. doi: 10.3390/ijms19010069. - DOI - PMC - PubMed
    1. Gasiorowska A., Wydrych M., Drapich P., Zadrozny M., Steczkowska M., Niewiadomski W., Niewiadomska G. The biology and pathobiology of glutamatergic, cholinergic, and dopaminergic signaling in the aging brain. Front. Aging Neurosci. 2021;13:654931. doi: 10.3389/fnagi.2021.654931. - DOI - PMC - PubMed
    1. Attwell D., Laughlin S.B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow. Metab. 2001;21:1133–1145. doi: 10.1097/00004647-200110000-00001. - DOI - PubMed

LinkOut - more resources