Inhibitory and excitatory neurotransmitter systems in depressed and healthy: A positron emission tomography and magnetic resonance spectroscopy study

Persson, Jonas; Wall, Anders; Weis, Ján; Gingnell, Malin; Antoni, Gunnar; Lubberink, Mark; Bodén, Robert

doi:10.1016/j.pscychresns.2021.111327

Cited by 15 publications

(13 citation statements)

References 38 publications

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“…Given the potential impact of GAD-autoantibodies, and the minor systemic effect of GABA secreted from beta-cells, the local levels of endogenous GABA in pancreatic islets could likely be affected without a detectable systemic decrease. Theoretically, local pancreatic GABA levels could be detected using magnetic resonance spectroscopy (MRS), as shown in the brain [ 16 ]. However, due to technical limitations related to disturbances from breathing motions, this technique would be difficult to apply for quantification within the pancreas.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Levels of Gamma Amino-Butyric Acid Are Correlated to Glutamic-Acid Decarboxylase Antibody Levels in Type 1 Diabetes

et al. 2021

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Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system (CNS) and outside of the CNS, found in the highest concentrations in immune cells and pancreatic beta-cells. GABA is gaining increasing interest in diabetes research due to its immune-modulatory and beta-cell stimulatory effects and is a highly interesting drug candidate for the treatment of type 1 diabetes (T1D). GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), one of the targets for autoantibodies linked to T1D. Using mass spectrometry, we have quantified the endogenous circulating levels of GABA in patients with new-onset and long-standing T1D and found that the levels are unaltered when compared to healthy controls, i.e., T1D patients do not have a deficit of systemic GABA levels. In T1D, GABA levels were negatively correlated with IL-1 beta, IL-12, and IL-15 15 and positively correlated to levels of IL-36 beta and IL-37. Interestingly, GABA levels were also correlated to the levels of GAD-autoantibodies. The unaltered levels of GABA in T1D patients suggest that the GABA secretion from beta-cells only has a minor impact on the circulating systemic levels. However, the local levels of GABA could be altered within pancreatic islets in the presence of GAD-autoantibodies.

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Section: Discussionmentioning

confidence: 99%

Endogenous Levels of Gamma Amino-Butyric Acid Are Correlated to Glutamic-Acid Decarboxylase Antibody Levels in Type 1 Diabetes

et al. 2021

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“…This suggests that impaired GABA functioning plays a role in glutamate excitotoxicity-induced depression. Despite this, a 2021 study found no deficit in GABA levels or receptor availability when combining MRS and flumazenil-labeled PET to examine anterior cortical and whole-brain GABA activity in MDD and controls [ 57 ]. In conclusion, despite significant imaging improvements and intense research over 20 years, the precise interactions of glutamatergic systems with other neurotransmitters in depression remain incompletely understood.…”

Section: Depressionmentioning

confidence: 99%

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

et al. 2022

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The monoamine model of depression has long formed the basis of drug development but fails to explain treatment resistance or associations with stress or inflammation. Recent animal research, clinical trials of ketamine (a glutamate receptor antagonist), neuroimaging research, and microbiome studies provide increasing evidence of glutamatergic dysfunction in depression and other disorders. Glutamatergic involvement across diverse neuropathologies including psychoses, neurodevelopmental, neurodegenerative conditions, and brain injury forms the rationale for this review. Glutamate is the brain’s principal excitatory neurotransmitter (NT), a metabolic and synthesis substrate, and an immune mediator. These overlapping roles and multiple glutamate NT receptor types complicate research into glutamate neurotransmission. The glutamate microcircuit comprises excitatory glutamatergic neurons, astrocytes controlling synaptic space levels, through glutamate reuptake, and inhibitory GABA interneurons. Astroglia generate and respond to inflammatory mediators. Glutamatergic microcircuits also act at the brain/body interface via the microbiome, kynurenine pathway, and hypothalamus–pituitary–adrenal axis. Disruption of excitatory/inhibitory homeostasis causing neuro-excitotoxicity, with neuronal impairment, causes depression and cognition symptoms via limbic and prefrontal regions, respectively. Persistent dysfunction reduces neuronal plasticity and growth causing neuronal death and tissue atrophy in neurodegenerative diseases. A conceptual overview of brain glutamatergic activity and peripheral interfacing is presented, including the common mechanisms that diverse diseases share when glutamate homeostasis is disrupted.

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“…Through gene set enrichment analysis, we found that the identified genes showed specific expression in brain tissue and cortical cells, providing credibility for the observed transcriptome–neuroimaging relationships [17]. Interestingly, except for the GMV- genes, all gene sets were enriched for inhibitory and excitatory neurons, which have previously been related to depression [39]. For example, the somatostatin (SST) interneuron is one of the major inhibitory neuron types, which primarily target the apical dendrites of pyramidal neurons and provide synaptic and extrasynaptic inhibition [40].…”

Section: Discussionmentioning

confidence: 91%

Gene expression has distinct associations with brain structure and function in major depressive disorder

Liu

Abdellaoui

Verweij

et al. 2022

Preprint

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Major depressive disorder (MDD) is associated with structural and functional brain abnormalities. MDD as well as brain anatomy and function are influenced by genetic factors, but the role of gene expression remains unclear. Here we investigated how cortical gene expression contributes to structural and functional brain abnormalities in MDD. We compared the gray matter volume and resting-state functional measures in a Chinese sample of 848 MDD patients and 749 healthy controls, and we then associated these case-control differences with cortical variation of gene expression. While whole gene expression was positively associated with structural abnormalities, it was negatively associated with functional abnormalities. We observed the relationships of expression levels with brain abnormalities for individual genes, and found that transcriptional correlates of brain structure and function showed opposite relations with gene dysregulation in postmortem cortical tissue from MDD patients. We further identified genes that were positively or negatively related to structural abnormalities as well as functional abnormalities. The MDD-related genes were enriched for brain tissue, cortical cells, and biological pathways. These findings suggest that distinct genetic mechanisms underlie structural and functional brain abnormalities in MDD, and highlight the importance of cortical gene expression for the development of cortical abnormalities

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Inhibitory and excitatory neurotransmitter systems in depressed and healthy: A positron emission tomography and magnetic resonance spectroscopy study

Cited by 15 publications

References 38 publications

Endogenous Levels of Gamma Amino-Butyric Acid Are Correlated to Glutamic-Acid Decarboxylase Antibody Levels in Type 1 Diabetes

Endogenous Levels of Gamma Amino-Butyric Acid Are Correlated to Glutamic-Acid Decarboxylase Antibody Levels in Type 1 Diabetes

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

Gene expression has distinct associations with brain structure and function in major depressive disorder

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