Glutamate and GABA Homeostasis and Neurometabolism in Major Depressive Disorder

Sarawagi, Ajay; Soni, Narayan Datt; Patel, Anant B.

doi:10.3389/fpsyt.2021.637863

Cited by 85 publications

(71 citation statements)

References 187 publications

(235 reference statements)

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“…However, among other things, research has revealed the relationships between amino acids homeostasis, neurotransmission, and lithium administration [15,22,23]. This is consistent with the fact that, according to some authors, the neurotransmission systems play an important role in the course of affective disorders [24,25].…”

Section: Introductionsupporting

confidence: 69%

The influence of lithium and/or selenium on plasma amino acids profile in rats

Kiełczykowska¹,

Musik²,

Luchowska-Kocot³

et al. 2021

Ann Agric Environ Med.

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Introduction. Selenium belongs to essential microelements and is used in agriculture. Lithium is used in medicine and the possibility of its exposure by environmental pollution has been reported. Both elements have been found to be connected with amino acids metabolism. Objective. The aim of the study was to compare the effect of lithium and selenium on plasma amino acids in rats, and to evaluate the influence of selenium in organisms exposed to lithium. Materials and method. The effect of selenium (0.5 mg/kg b.w., orally as Na 2 SeO 3 ) and/or lithium (2.7 mg/kg b.w., orally as Li 2 CO 3 ) given for 6 weeks on the plasma profile of selected amino acids in rats was studied. The concentrations of amino acids were determined using ion exchange chromatography with the aid of an amino acids analyzer AAA400. Results. A significant effect of lithium on plasma amino acids profile was found in rats, much greater than for selenium. Selenium treatment slightly increased Tau, Phe, Tyr, Ala, Trp, Ser and Gln, while Lys and Orn were enhanced in a significant way. In contrast, Li-treatment caused a well-marked increase in Phe, Orn, Ala, His, Trp, Asp and Gln, whereas all the others were only slightly increased. Co-treatment resulted in a significant increase in Orn and Trp, a slight enhancement of Phe, Lys and His, while the rest remained unchanged. Conclusions. A significant effect of lithium alone on plasma amino acids profile in animals was demonstrated, with a much less influence of selenium alone. Co-treatment generally resulted in a slight or no effect. The slight selenium influence seems important regarding its agricultural application and the growing interest in its supplementation. Results concerning lithium could contribute to the research regarding the mechanism of Li action.

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Section: Introductionsupporting

confidence: 69%

The influence of lithium and/or selenium on plasma amino acids profile in rats

Kiełczykowska¹,

Musik²,

Luchowska-Kocot³

et al. 2021

Ann Agric Environ Med.

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“…Reduction in BDNF and GABA neurotransmission co-occur in the mPFC tissues and has been repeatedly seen in animal models and human subjects, and this has been associated with anhedonia and anxiety [ 54 , 79 – 82 ]. In addition, treatment with antidepressants and anti-anxiety agents, as well as repetitive transcranial magnetic stimulation treatment has been shown to enhance GABA and BDNF expression in depression [ 83 , 84 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of the chemical-material basis and molecular mechanisms for the classic herbal formula of Lily Bulb and Rehmannia Decoction in alleviating depression

et al. 2021

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Background Lily Bulb and Rehmannia Decoction (LBRD), is a traditional Chinese formula that has been shown to be safe and effective against depression; however, its material basis and pharmacological mechanisms remain unknown. Methods Here, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) and high-performance liquid chromatography (HPLC) were used to identify the chemical spectrum and qualitatively identify the major active ingredients in the LBRD standard decoction, respectively. Subsequently, we assessed the behavior, neuronal function and morphology, neurotransmitter levels, hypothalamic–pituitary–adrenal (HPA)-axis associated hormones, inflammatory cytokine levels, and miRNA/mRNA expression alterations in an in vitro/vivo depression model treated by the LBRD standard decoction. Finally, miRNA/mRNA regulatory networks were created through bioinformatics analysis, followed by functional experiments to verify its role in LBRD standard decoction treatment. Results A total of 32 prototype compounds were identified in the LBRD standard decoction, and the average quality of verbascoside in the fresh lily bulb decoction, fresh raw Rehmannia juice, and the LBRD standard decoction were 0.001264%, 0.002767%, and 0.009046% (w/w), respectively. Administration of the LBRD standard decoction ameliorated chronic unpredictable mild stress (CUMS)-induced depression-like phenotypes and protected PC12 cells against chronic corticosterone (CORT)-induced injury. The levels of neurotransmitter, cytokine, stress hormones and neuronal morphology were disrupted in the depression model, while LBRD standard decoction could work on these alterations. After LBRD standard decoction administration, four differentially expressed miRNAs, rno-miR-144-3p, rno-miR-495, rno-miR-34c-5p, and rno-miR-24-3p, and six differentially expressed mRNAs, Calml4, Ntrk2, VGAT, Gad1, Nr1d1, and Bdnf overlapped in the in vivo/vitro depression model. Among them, miR-144-3p directly mediated GABA synthesis and release by targeting Gad1 and VGAT, and miR-495 negatively regulated BDNF expression. The LBRD standard decoction can reverse the above miRNA/mRNA network-mediated GABA and BDNF expression in the in vivo/vitro depression model. Conclusion Collectively, the multi-components of the LBRD standard decoction altered a series of miRNAs in depression through mediating GABAergic synapse, circadian rhythm, and neurotrophic signaling pathway etc., thereby abolishing inhibitory/excitatory neurotransmitter deficits, recovering the pro-/anti-inflammatory cytokine levels and regulating the HPA-axis hormone secretion to achieve balance of the physiological function of the whole body.

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“…A growing literature supports the notion that a widespread network dysconnectivity, as opposed to aberrant responses within select brain regions, is what characterizes and possibly drives pathophysiological changes associated with MDD ( 35 , 38 ). Behind these changes, a variety of molecular processes related to glutamate cycling and release may be implicated, including the decreased expression NMDA-Rs ( 39 – 41 ), AMPA-Rs ( 41 , 42 ), or mGluRs ( 43 ), which have been reported both in humans and animal models of depression, as well as in postmortem brains of suicide victims ( 39 , 44 ).…”

Section: Glutamatergic Neurocircuitry Dysfunction In Major Depressive...mentioning

confidence: 98%

“…For the purposes of this review, we define cortical pathways as those with at least one node situated in the cerebral cortex, and subcorticolimbic pathways as those with no nodes in the cerebral cortex. The cortical glutamatergic pathways can be further subdivided into five major arcs ( 35 , 36 ), illustrated in Figure 1 . Similarly, the subcorticolimbic glutamatergic pathways can be categorized into hippocampal and amygdalar, where HPC and AMYG are the central limbic nodes ( 37 ), illustrated in Figure 2 .…”

Section: Overview Of Glutamatergic Neurocircuitrymentioning

confidence: 99%

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Intrinsic Connectivity Networks of Glutamate-Mediated Antidepressant Response: A Neuroimaging Review

et al. 2022

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Conventional monoamine-based pharmacotherapy, considered the first-line treatment for major depressive disorder (MDD), has several challenges, including high rates of non-response. To address these challenges, preclinical and clinical studies have sought to characterize antidepressant response through monoamine-independent mechanisms. One striking example is glutamate, the brain's foremost excitatory neurotransmitter: since the 1990s, studies have consistently reported altered levels of glutamate in MDD, as well as antidepressant effects following molecular targeting of glutamatergic receptors. Therapeutically, this has led to advances in the discovery, testing, and clinical application of a wide array of glutamatergic agents, particularly ketamine. Notably, ketamine has been demonstrated to rapidly improve mood symptoms, unlike monoamine-based interventions, and the neurobiological basis behind this rapid antidepressant response is under active investigation. Advances in brain imaging techniques, including functional magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, enable the identification of the brain network-based characteristics distinguishing rapid glutamatergic modulation from the effect of slow-acting conventional monoamine-based pharmacology. Here, we review brain imaging studies that examine brain connectivity features associated with rapid antidepressant response in MDD patients treated with glutamatergic pharmacotherapies in contrast with patients treated with slow-acting monoamine-based treatments. Trends in recent brain imaging literature suggest that the activity of brain regions is organized into coherent functionally distinct networks, termed intrinsic connectivity networks (ICNs). We provide an overview of major ICNs implicated in depression and explore how treatment response following glutamatergic modulation alters functional connectivity of limbic, cognitive, and executive nodes within ICNs, with well-characterized anti-anhedonic effects and the enhancement of “top-down” executive control. Alterations within and between the core ICNs could potentially exert downstream effects on the nodes within other brain networks of relevance to MDD that are structurally and functionally interconnected through glutamatergic synapses. Understanding similarities and differences in brain ICNs features underlying treatment response will positively impact the trajectory and outcomes for adults suffering from MDD and will facilitate the development of biomarkers to enable glutamate-based precision therapeutics.

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Glutamate and GABA Homeostasis and Neurometabolism in Major Depressive Disorder

Cited by 85 publications

References 187 publications

The influence of lithium and/or selenium on plasma amino acids profile in rats

The influence of lithium and/or selenium on plasma amino acids profile in rats

Integrated analysis of the chemical-material basis and molecular mechanisms for the classic herbal formula of Lily Bulb and Rehmannia Decoction in alleviating depression

Intrinsic Connectivity Networks of Glutamate-Mediated Antidepressant Response: A Neuroimaging Review

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