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Glutamate and GABA signalling components in the human brain and in immune cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. (Bryndis Birnir)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glutamate and γ-aminobutyric acid (GABA) are the principal excitatory and inhibitory neurotransmitters in the central nervous system (CNS). They both can activate their ionotropic and metabotropic receptors. Glutamate activates ionotropic glutamate receptors (iGlu - AMPA, kainate and NMDA receptors) and GABA activates GABA-A receptors which are modulated by many types of drugs and substances including alcohol. Using real time quantitative polymerase chain reaction, I have shown that iGlu and/or GABA-A receptor subunits were expressed in the hippocampus dentate gyrus (HDG), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), central amygdala (CeA), caudate and putamen of the human brain and their expression was altered by chronic excessive alcohol consumption. It indicates that excitatory and inhibitory neurotransmission may have been altered in the brain of human alcoholics. It is possible that changes in one type of neurotransmitter system may drive changes in another. These brain regions also play a role in brain reward system. Any changes in them may lead to changes in the normal brain functions.

Apart from the CNS, glutamate and GABA are also present in the blood and can be synthesised by pancreatic islet cells and immune cells. They may act as immunomodulators of circulating immune cells and can affect immune function through glutamate and GABA receptors. I found that T cells from human, rat and mouse lymph nodes expressed the mRNAs and proteins for specific GABA-A receptor subunits. GABA-evoked transient and tonic currents recorded using the patch clamp technique demonstrate the functional GABA-A channel in T cells. Furthermore, the mRNAs for specific iGlu, GABA-A and GABA-B receptor subunits and chloride cotransporters were detected in peripheral blood mononuclear cells (PBMCs) from men, non-pregnant women, healthy and depressed pregnant women. The results indicate that the expression of iGlu, GABA-A and GABA-B receptors is related to gender, pregnancy and mental health and support the notion that glutamate and GABA receptors may modulate immune function. Intra- and interspecies variability exists in the expression and it is further influenced by physiological conditions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 81 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1218
National Category
Medical and Health Sciences Neurosciences Cell and Molecular Biology Physiology Immunology in the medical area Immunology
Research subject
Neuroscience; Immunology
Identifiers
URN: urn:nbn:se:uu:diva-282422ISBN: 978-91-554-9558-9 (print)OAI: oai:DiVA.org:uu-282422DiVA: diva2:918767
Public defence
2016-06-02, C2: 301, BMC, Husargatan 3, 751 24, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-05-09 Created: 2016-04-05 Last updated: 2016-05-09
List of papers
1. Selective increases of AMPA, NMDA, and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics
Open this publication in new window or tab >>Selective increases of AMPA, NMDA, and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics
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2014 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 8, 11- p.Article in journal (Refereed) Published
Abstract [en]

Glutamate is the main excitatory transmitter in the human brain. Drugs that affect the glutamatergic signaling will alter neuronal excitability. Ethanol inhibits glutamate receptors. We examined the expression level of glutamate receptor subunit mRNAs in human post-mortem samples from alcoholics and compared the results to brain samples from control subjects. RNA from hippocampal dentate gyrus (HP-DG), orbitofrontal cortex (OFC), and dorso-lateral prefrontal cortex (DL-PFC) samples from 21 controls and 19 individuals with chronic alcohol dependence were included in the study. Total RNA was assayed using quantitative RT-PCR. Out of the 16 glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA2 and GluA3; three kainate receptor subunits GluK2, GluK3 and GluK5 and five NMDA (N-methyl-D-aspartate) receptor subunits GluN1, GluN2A, GluN2C, GluN2D, and GluN3A were significantly increased in the HP-DG region in alcoholics. In the OFC, mRNA encoding the NMDA receptor subunit GluN3A was increased, whereas in the DL-PFC, no differences in mRNA levels were observed. Our laboratory has previously shown that the expression of genes encoding inhibitory GABA-A receptors is altered in the HP-DG and OFC of alcoholics (Jin et al., 2011). Whether the changes in one neurotransmitter system drives changes in the other or if they change independently is currently not known. The results demonstrate that excessive long-term alcohol consumption is associated with altered expression of genes encoding glutamate receptors in a brain region-specific manner. It is an intriguing possibility that genetic predisposition to alcoholism may contribute to these gene expression changes.

National Category
Physiology Neurosciences
Identifiers
urn:nbn:se:uu:diva-219489 (URN)10.3389/fncel.2014.00011 (DOI)000331053400001 ()24523671 (PubMedID)
Available from: 2014-03-03 Created: 2014-03-03 Last updated: 2017-12-05Bibliographically approved
2. Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics
Open this publication in new window or tab >>Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics
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2014 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 8, 288- p.Article in journal (Refereed) Published
Abstract [en]

The central amygdala (CeA) has a role for mediating fear and anxiety responses. It is also involved in emotional imbalance caused by alcohol abuse and dependence and in regulating relapse to alcohol abuse. Growing evidences suggest that excitatory glutamatergic and inhibitory gamma-aminobutyric acid-ergic (GABAergic) transmissions in the CeA are affected by chronic alcohol exposure. Human post-mortem CeA samples from male alcoholics (n = 9) and matched controls (n = 9) were assayed for the expression level of ionotropic glutamate and GABA-A receptors subunit mRNAs using quantitative real-time reverse transcription-PCB (RT-qPCR). Our data revealed that out of the 16 ionotropic glutamate receptor subunits, mRNAs encoding two AMPA P-amino-3-(3-hydroxy-5-methyl-isoxazol-4-y1)propanoic acid] receptor subunits GluA1 and GluA4; one kainate receptor subunit GluK2; one NMDA (N-methyl-D-aspartate) receptor subunit GluN2D and one delta receptor subunit GluD2 were significantly decreased in the CeA of alcoholics. In contrast, of the 19 GABA-A receptor subunits, only the mRNA encoding the a2 subunit was significantly down-regulated in the CeA of the alcoholics as compared with control subjects. Our findings imply that the down-regulation of specific ionotropic glutamate and GABA-A receptor subunits in the CeA of alcoholics may represent one of the molecular substrates underlying the new balance between excitatory and inhibitory neurotransmission in alcohol dependence.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-239603 (URN)10.3389/fncel.2014.00288 (DOI)000344465400002 ()
Available from: 2014-12-30 Created: 2014-12-29 Last updated: 2017-12-05Bibliographically approved
3.
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4. Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes
Open this publication in new window or tab >>Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 8, e42959- p.Article in journal (Refereed) Published
Abstract [en]

γ-aminobutyric acid (GABA) is the most prominent neuroinhibitory transmitter in the brain, where it activates neuronalGABA-A receptors (GABA-A channels) located at synapses and outside of synapses. The GABA-A receptors are primarytargets of many clinically useful drugs. In recent years, GABA has been shown to act as an immunomodulatory molecule. Wehave examined in human, mouse and rat CD4+ and CD8+ T cells which subunit isoforms of the GABA-A channels areexpressed. The channel physiology and drug specificity is dictated by the GABA-A receptor subtype, which in turn isdetermined by the subunit isoforms that make the channel. There were 5, 8 and 13 different GABA-A subunit isoformsidentified in human, mouse and rat CD4+ and CD8+ T cells, respectively. Importantly, the γ2 subunit that imposesbenzodiazepine sensitivity on the GABA-A receptors, was only detected in the mouse T cells. Immunoblots andimmunocytochemistry showed abundant GABA-A channel proteins in the T cells from all three species. GABA-activatedwhole-cell transient and tonic currents were recorded. The currents were inhibited by picrotoxin, SR95531 and bicuculline,antagonists of GABA-A channels. Clearly, in both humans and rodents T cells, functional GABA-A channels are expressed butthe subtypes vary. It is important to bear in mind the interspecies difference when selecting the appropriate animal modelsto study the physiological role and pharmacological properties of GABA-A channels in CD4+ and CD8+ T cells and whenselecting drugs aimed at modulating the human T cells function.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-172532 (URN)10.1371/journal.pone.0042959 (DOI)000307789700016 ()
Available from: 2012-04-11 Created: 2012-04-11 Last updated: 2017-12-07Bibliographically approved
5. Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health
Open this publication in new window or tab >>Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health
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2015 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 3, 575-585 p.Article in journal (Refereed) Published
Abstract [en]

AIM: The concept of nerve-driven immunity recognizes a link between the nervous and the immune system. γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain and receptors activated by GABA can be expressed by immune cells. Here we examined if the expression of GABA receptors and chloride transporters in human peripheral mononuclear cells (PBMCs) were influenced by gender, pregnancy or mental health.

METHODS: We used RT-qPCR to determine the mRNA expression level in men (n=16), non-pregnant women (n=19), healthy pregnant women (n=27) and depressed pregnant women (n=15).

RESULTS: The ρ2 subunit had the most prominent expression level of the GABA-A receptor subunits in all samples. The δ and ρ2 subunits were up-regulated by pregnancy whereas the ε subunit was more frequently expressed in healthy pregnant women than non-pregnant women who, in-turn, commonly expressed the α6 and the γ2 subunits. The β1 and ε subunits expression was altered by depression in pregnant women. The GABA-B1 receptor was up-regulated by depression in pregnant women while the transporters NKCC1 and KCC4 were down-regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMCs.

CONCLUSION: The results demonstrate the impact gender, pregnancy and mental health have on expression of GABA receptors plus chloride transporters expressed in human PBMCs.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-240372 (URN)10.1111/apha.12440 (DOI)000348531600007 ()25529063 (PubMedID)
Available from: 2015-01-07 Created: 2015-01-07 Last updated: 2017-12-05
6. AMPA, NMDA and kainate glutamate receptor subunits are expressed in human peripheral blood mononuclear cells (PBMCs) where the expression of GluK4 is altered by pregnancy and GluN2D by depression in pregnant women
Open this publication in new window or tab >>AMPA, NMDA and kainate glutamate receptor subunits are expressed in human peripheral blood mononuclear cells (PBMCs) where the expression of GluK4 is altered by pregnancy and GluN2D by depression in pregnant women
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2017 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 305, 51-58 p.Article in journal (Refereed) Published
Abstract [en]

The amino acid glutamate opens cation permeable ion channels, the iGlu receptors. These ion channels are abundantly expressed in the mammalian brain where glutamate is the main excitatory neurotransmitter. The neurotransmitters and their receptors are being increasingly detected in the cells of immune system. Here we examined the expression of the 18 known subunits of the iGlu receptors families; alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, N-methyl-D-aspartate (NMDA) and delta in human peripheral blood mononuclear cells (PBMCs). We compared the expression of the subunits between four groups: men, non-pregnant women, healthy pregnant women and depressed pregnant women.

Out of 18 subunits of the iGlu receptors, mRNAs for 11 subunits were detected in PBMCs from men and nonpregnant women; AMPA: GluA3, GluA4, kainate: GluK2, GluK4, GluK5, NMDA: GluN1, GluN2C, GluN2D, GluN3A, GluN3B, and delta: GluD1. In the healthy and the depressed pregnant women, in addition, the delta GluD2 subunit was identified. The mRNAs for GluK4, GluK5, GluN2C and GluN2D were expressed at a higher level than other subunits. Gender, pregnancy or depression during pregnancy altered the expression of GluA3, GluK4, GluN2D, GluN3B and GluD1 iGlu subunit mRNAs. The greatest changes recorded were the lower GluA3 and GluK4 mRNA levels in pregnant women and the higher GluN2D mRNA level in healthy but not in depressed pregnant women as compared to non-pregnant individuals. Using subunit specific antibodies, the GluK4, GluK5, GluNl, GluN2C and GluN2D subunit proteins were identified in the PBMCs. The results show expression of specific iGlu receptor subunit in the PBMCs and support the idea of physiology-driven changes of iGlu receptors subtypes in the immune cells.

Keyword
Glutamate, iGluR subunits, Immune cells, Pregnancy, Depression, Physiology-driven changes
National Category
Medical and Health Sciences Neurosciences
Identifiers
urn:nbn:se:uu:diva-282410 (URN)10.1016/j.jneuroim.2017.01.013 (DOI)000397694200009 ()28284346 (PubMedID)
Funder
Swedish Research Council, 521-2012-1789
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2017-05-16Bibliographically approved

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