Introductory Chapter: GABA/Glutamate Balance: A Key for Normal Brain Functioning

Full text

3,350+
OPEN ACCESS BOOKS
108,000+
INTERNAT IONAL
AUTHORS AND EDITORS 114 + MILLION
DOWNLOADS
BOOKS
DELIVERED TO
151 COUNTRIES
AUTHORS AMONG
TOP 1%
MOST CITED SCIENTI ST
12.2%
AUTHORS AND EDITORS
FROM TOP 500 UNIVERSITIES
Selection of our books indexed in the
Book Citation Index in We b of Science ™
Co re Collection (BKCI)
Chapter fr om the boo k
GABA And Glutamate - Ne w Deve lopme nts In Neurotrans missio n
Re search
Downloade d fro m: http://www.intechopen.com/boo ks /gaba-and-g lutamate-new-
de velopments-in-neurotransmis s ion-re search
PUBLISH ED B Y
World's largest Science,
Technology & Medicine
Open Access book publisher
Interested in publishing with IntechOpen?
Contact us at book.dep artment@intechope n.com

Chapter 1
Introductory Chapter: GABA/Glutamate Balance: A Key
for Normal Brain Functioning
Janko Samardzic, Dragana Jadzic, Boris Hencic,
Jasna Jancic and Dubravka Svob Strac
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/intechopen.74023
Provisional chapter
DOI: 10.5772/intechopen.74023
© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Introductory Chapter: GABA/Glutamate Balance: A Key
for Normal Brain Functioning
JankoSamardzic, DraganaJadzic, BorisHencic,
JasnaJancic and Dubravka SvobStrac
Additional information is available at the end of the chapter
1. Introduction
The basis of information transfer in the mammalian central nervous system (CNS) consists of
excitation and inhibition of neuronal networks. The messengers responsible for propagating
these excitatory and inhibitory actions are amino acid neurotransmiers [1]. The principal
excitatory neurotransmier is glutamate, while the principle inhibitory neurotransmier is
gamma-aminobutyric acid (GABA). Coordination between these two principal neurotrans-
miers ensures adequate rhythmic activity, which may involve either a single neuron or mul-
tiple neuronal groups, thus altering synaptic plasticity and ensuring a normal functioning
of CNS [2]. As this spatiotemporal framework of dierent paerns in neural oscillations is
essential for information processing throughout the brain [3], the deviations in normal activ-
ity of either system or their interactions are associated with a number of neurological and
psychiatric diseases [4].
The GABA/glutamate functional balance could be achieved by homeostatic control of
presynaptic elements such as glutamate and GABA release, which could be the result
of changes in their metabolism (synthesis or degradation involving various enzymes),
compartmentation, and recycling (involving plasma transporters) and in the amounts of
transmitters available for release from synaptic vesicles (involving vesicular transport-
ers). However, it is generally considered that homeostatic plasticity mechanisms in the
brain are mediated primarily by regulation of expression and function of glutamate and
GABA receptors [5].
© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

2. GABA and its receptors
Every third chemical synapse in the brain uses neurotransmier GABA as an integral part of
the neurotransmission process. GABA mediates its eects via two types of receptors: iono-
tropic GABAA and metabotropic GABAB receptors [6]. Although a third type of GABA recep-
tor with pharmacological specicities has been identied, the term GABAС has not received
broad consensus among experts. Additionally, the International Union of Basic and Clinical
Pharmacology (IUPHAR) has classied GABAC as a type of GABAA receptor [7].
GABAA receptors generally contain chloride ion channels but can, in varying degrees, also
contain calcium, sodium, and potassium channels. GABAA receptors mediate the majority of
GABA inhibitory actions in the CNS [4]. They are pentameric transmembrane receptors made
up of 5 subunit proteins that form an ion channel selectively permeable to chloride anions.
Although mainly localized on postsynaptic membranes, they can also be found extrasyn-
aptically, especially GABAA receptors containing α4, α5, or α6 subunits [8]. Unexpectedly,
GABAA receptors have also been found on glial cells, potentially providing adaptational sup-
port for adjacent neurons [9]. Activation of GABAA receptors leads to a change in the con-
formational state of associated ion channels, resulting in increased permeability to chloride
ions. GABAergic mechanisms are also involved in metabolic processes [10], and a negative
correlation between the intensity of GABAergic neurotransmission and metabolic processes
in cerebral tissue has been established. So far, 19 subunits of GABAA receptors have been
cloned and classied into several structurally related subfamilies (α 1–6, β 1–3, γ 1–3, δ, ε, θ,
π, ρ 1–3). The most frequently found GABAA receptor composition is an aggregate composed
of two α, two β, and one γ subunit [4]. Receptors that, in addition to two α and two β subunits,
contain some other non-γ subunit are rare. Receptors composed only of α and β isoforms
also exist. The subunit composition determines the functional and pharmacological proper-
ties of GABAA receptors. For example, α1 GABAA receptors mediate sedative and anticonvul-
sant actions, whereas the α2 subunit is responsible for anxiolytic action of benzodiazepines.
Zolpidem, a commonly prescribed sedative for sleep initiation, has a high binding anity for
GABAA receptors containing the α1 subunit [11].
GABA action through GABAA receptors results in chloride channel opening and increased
postsynaptic membrane permeability. In addition to the well-determined benzodiazepine
binding site, at least 13 dierent and structurally specic sites on the GABAA receptors have
been identied: (1) GABA and other agonist-binding sites, as well as competitive antago-
nists; (2) picrotoxin site near ion channel; (3) barbiturates binding site; (4) neuroactive steroids
binding site; (5) ethanol binding site; (6) inhalation anesthetics stereoselective binding sites;
(7) furosemide diuretic binding site; (8) Zn2+ ion binding site; (9) other divalent cation binding
sites; (10) La3+ ions site; (11) sites for phosphorylation of specic protein kinases; (12) phos-
pholipid-binding sites; and (13) sites involved in interaction of GABAA receptor and micro-
tubules, which promote receptor grouping on postsynaptic membranes [12]. Modulators of
GABAA receptor complex interact with these binding sites in three possible ways: positive
allosteric modulators that potentiate chloride ion ux (agonists), negative modulators that
reduce GABA-induced chloride ion ux (inverse agonists), and neutral allosteric modulators
that competitively block the eects of these two types of agonists-antagonists.
GABA And Glutamate - New Developments In Neurotransmission Research2

B

are pre- and postsynaptic G-protein-coupled receptors that negatively modulate adenylyl
cyclase and inositol triphosphate synthesis. Heterodimeric structure as a result of GABAB1
and GABAB2 subunit assembly is necessary for appropriate GABAB receptor function. The

subunit is important for the interaction with the G-proteins. GABAB receptor activation pro-
duces a cascade of signals that result in activation and/or inhibition of voltage-dependent
calcium channels. GABAB
     B

      13 14].
-
1516].
3. Glutamate and its receptors
-
ent in over 90% of all synaptic connections in the human brain and is essential for a wide variety
17
      
 
in heterotetrameric or homotetrameric receptors. The three types of ionotropic receptors are
N-methyl-

18].
-
lective cation channel. The opening and closing of the channel are primarily gated by ligand
binding but are also voltage-dependent. Extracellular magnesium and zinc ions can bind to
-
       

19-

          20 
     -


   21-

       22   
-
2325].
Introductory Chapter: GABA/Glutamate Balance: A Key for Normal Brain Functioning
http://dx.doi.org/10.5772/intechopen.74023
3

AMPA receptors (AMPAR) are composed of four types of subunits, designated as GluA1,
GluA2, GluA3, and GluA4 [26]. These receptors are heterotetrameric, containing GluA2
and either GluA1, GluA3, or GluA4 subunits in a “dimer of dimers” structure [27, 28]. Each
AMPAR consists of four subunits which make up four binding sites to which an agonist (such
as glutamate) can bind. The channel opens when two binding sites are simultaneously occu-
pied, and the current increases as more binding sites become occupied [29]. Once opened, the
channel may undergo rapid desensitization and current termination. Since AMPARs open and
close quickly (1 ms), they are responsible for fast excitatory synaptic transmission in the CNS
[30]. The GluA2 subunit regulates whether the AMPAR is permeable to calcium and other
cations, such as sodium and potassium. If receptor does not contain a GluA2, the AMPAR will
be permeable to calcium, sodium, and potassium. Both NMDA and AMPA ion channels are
important for plasticity and synaptic transmission at many postsynaptic membranes.
Kainate receptors (KAR) are heteromeric receptors assembled from four subunits, formerly
referred to as GluR5, GluR6, GluR7, KA1, and KA2 but now named GluK1, GluK2, GluK3, GluK4,
and GluK5, and grouped into low anity (GluK1–3) and high anity (GluK4–5) receptors. Each
subunit has a large extracellular N-terminal domain, four helical transmembrane domains (M1–M4),
and an intracellular C-terminal domain. GluK1–3 subunits can form both homomeric and het-
eromeric receptors, but GluK4 and GluK5 subunits can form only heteromeric functional ion
channels together with GluK1–3 subunits. Despite their ion channel structure, KAR can also acti-
vate metabotropic signaling through noncanonical G-protein-coupled cascade. They are widely
distributed in the brain and can be localized at pre-, post-, and/or extrasynaptic sites. Although
KAR are less studied than AMPAR or NMDAR, it is not known that they are multifunctional
neuronal modulators which play signicant roles in health and disease [31].
Metabotropic glutamate receptors (mGluR) have a G-protein-linked receptor structure consist-
ing of seven transmembrane domains with an extracellular N-terminal and an intracellular
COOH terminal. When glutamate binds to a metabotropic receptor, it activates a postsynaptic
intracellular G-protein, which eventually results in the opening of a membrane channel for sig-
nal transmission. Furthermore, G protein activation also triggers functional changes in the cyto-
plasm, resulting in gene expression and protein synthesis. For this reason, mGluR is generally
considered slower acting channels than the ionotropic glutamate receptors. To date, three groups
of mGluR exist. Group I receptors are coupled with phospholipase C, producing diacylglycerol
and inositol triphosphate as second messengers. They are mainly expressed on the postsynaptic
membrane. Group I receptors are involved in learning and memory, addiction, motor regula-
tion, and Fragile X syndrome [32]. Groups II and III are negatively coupled to adenylyl cyclase.
Impaired functioning of group II metabotropic receptors has been linked to anxiety, schizophre-
nia, and Alzheimer’s disease. Group III metabotropic receptors also inhibit neurotransmier
release but are positioned presynaptically. They are found within the hippocampus and hypo-
thalamus and may play a role in Parkinson’s disease and anxiety disorders [33].
4. Conclusion and clinical implications
The adequate coordination of GABA and glutamate is essential to the normal functioning for
the most complex brain processes. Decreased or increased GABA activity is associated with a
GABA And Glutamate - New Developments In Neurotransmission Research4

number of neurological and psychiatric diseases. The GABAergic synapse is the site of action
of several dierent classes of drugs that modulate inhibitory neurotransmission and are used
in the pharmacotherapy of anxiety and sleep disorders, epilepsy, alcohol withdrawal, and
induction and maintenance of anesthesia [34]. Moreover, glutamate dysfunction is also corre-
lated with a wide range of nervous system disorders, such as Alzheimer’s disease, and neuro-
psychiatric disorders, including schizophrenia, pain disorders, drug addiction, and traumatic
brain and spinal cord injuries [35]. Given the importance of equilibrium of these two systems
for neuronal excitability, synaptic plasticity, and cognitive functions such as learning and
memory, as well as its involvement in the mood, feeding behavior, reproductive functions,
pain sensitivity, aging, etc. [36], it is not surprising that the development of current and pro-
spective pharmaceuticals, including anxiolytics, antidepressants, antipsychotics, antiepilep-
tics, antidementia, and many other drugs, relies increasingly on GABA/glutamate balance.
Acknowledgements
Janko Samardzic’s and Jasna Jancic’s work has been supported by the Ministry of Education,
Science and Technological Development of the Republic of Serbia (Grant nos. 175076 and
175031). The authors declare that there are no competing interests regarding the publication
of this chapter.
Author details
Janko Samardzic1*, Dragana Jadzic2, Boris Hencic1, Jasna Jancic3 and Dubravka Svob Strac4
*Address all correspondence to: jankomedico@yahoo.es
1 Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty,
University of Belgrade, Belgrade, Serbia
2 Department of Biomedical Sciences, Neuropsychopharmacology Sect, University of
Cagliari, Cagliari, Italy
3 Clinic of Neurology and Psychiatry for Children and Youth, Medical Faculty, University of
Belgrade, Belgrade, Serbia
4 Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer
Boskovic Institute, Zagreb, Croatia
References
[1] Petro OA. GABA and glutamate in the human brain. The Neuroscientist. 2002;8(6):562-573
[2] Foster AC, Kemp JA. Glutamate- and GABA-based CNS therapeutics. Current Opinion
in Pharmacology. 2006;6(1):7-17
Introductory Chapter: GABA/Glutamate Balance: A Key for Normal Brain Functioning
http://dx.doi.org/10.5772/intechopen.74023
5

[3] Buzsaki G, Draguhn A. Neuronal oscillations in cortical networks. Science. 2004;
304(5679):1926-1929
[4] Jacob TC, Moss SJ, Jurd R. GABA(A) receptor tracking and its role in the dynamic
modulation of neuronal inhibition. Nature Reviews. Neuroscience. 2008;9(5):331-343
[5] Erickson JD, De Gois S, Varoqui H, Schafer MK, Weihe E. Activity-dependent regu-
lation of vesicular glutamate and GABA transporters: A means to scale quantal size.
Neurochemistry International. 2006;48(6-7):643-649
[6] Chebib M, Johnston GA. The ‘ABC’ of GABA receptors: A brief review. Clinical and
Experimental Pharmacology & Physiology. 1999;26(11):937-940
[7] Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of gamma-
aminobutyric acid(A) receptors: Classication on the basis of subunit composition, phar-
macology, and function. Update. Pharmacological Reviews. 2008;60(3):243-260
[8] Fritschy JM, Brunig I. Formation and plasticity of GABAergic synapses: Physiological
mechanisms and pathophysiological implications. Pharmacology & Therapeutics. 2003;
98(3):299-323
[9] Lin SC, Bergles DE. Synaptic signaling between neurons and glia. Glia. 2004;47(3):290-298
[10] Korpi ER, Grunder G, Luddens H. Drug interactions at GABA(A) receptors. Progress in
Neurobiology. 2002;67(2):113-159
[11] Vlainić J, Jembrek MJ, Strac DS, Pericić D. The eects of zolpidem treatment and with-
drawal on the in vitro expression of recombinant alpha1beta2gamma2s GABA(A) recep-
tors expressed in HEK 293 cells. Naunyn-Schmiedeberg's Archives of Pharmacology.
2010;382(3):201-212
[12] Chebib M, Johnston GA. GABA-activated ligand gated ion channels: Medicinal chemis-
try and molecular biology. Journal of Medicinal Chemistry. 2000;43(8):1427-1447
[13] Beler B, Kaupmann K, Mosbacher J, Gassmann M. Molecular structure and physiologi-
cal functions of GABA(B) receptors. Physiological Reviews. 2004;84(3):835-867
[14] Heaney CF, Kinney JW. Role of GABA(B) receptors in learning and memory and neuro-
logical disorders. Neuroscience and Biobehavioral Reviews. 2016;63:1-28
[15] Cryan JF, Kaupman K. Don't worry ‘B’ happy!: A role for GABAB receptors in anxiety
and depression. Trends in Pharmacological Sciences. 2005;26(1):36-43
[16] Bowery NG. GABAB receptor: A site of therapeutic benet. Current Opinion in Pharma-
cology. 2006;6(1):37-43
[17] Meldrum BS. Glutamate as a neurotransmier in the brain: Review of physiology and
pathology. The Journal of Nutrition. 2000;130(4S):1007S-10015S
[18] Lesage A, Steckler T. Metabotropic glutamate mGlu1 receptor stimulation and blockade:
Therapeutic opportunities in psychiatric illness. European Journal of Pharmacology.
2010;639(1-3):2-16
[19] Paolei P, Neyton J. NMDA receptor subunits: Function and pharmacology. Current
Opinion in Pharmacology. 2007;7(1):39-47
GABA And Glutamate - New Developments In Neurotransmission Research6

[20] Kleckner NW, Dingledine R. Requirement for glycine in activation of NMDA-receptors
expressed in Xenopus oocytes. Science. 1988;241(4867):835-837
[21] Lee MC, Ting KK, Adams S, Brew BJ, Chung R, Guillemin GJ. Characterisation of the
expression of NMDA receptors in human astrocytes. PLoS One. 2010;5(11):e14123
[22] Barco A, Bailey CH, Kandel ER. Common molecular mechanisms in explicit and implicit
memory. Journal of Neurochemistry. 2006;97(6):1520-1533
[23] Chen HS, Lipton SA. The chemical biology of clinically tolerated NMDA receptor antag-
onists. Journal of Neurochemistry. 2006;97(6):1611-1626
[24] Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine
and beyond. Nature Reviews. Drug Discovery. 2006;5(2):160-170
[25] Koch HJ, Szecsey A, Haen E. NMDA-antagonism (memantine): An alternative pharma-
cological therapeutic principle in Alzheimer’s and vascular dementia. Current Pharma-
ceutical Design. 2004;10(3):253-259
[26] Song I, Huganir RL. Regulation of AMPA receptors during synaptic plasticity. Trends in
Neurosciences. 2002;25(11):578-588
[27] Mayer ML. Glutamate receptor ion channels. Current Opinion in Neurobiology. 2005;
15(3):282-288
[28] Greger IH, Zi EB, Penn AC. Molecular determinants of AMPA receptor subunit assem-
bly. Trends in Neurosciences. 2007;30(8):407-416
[29] Rosenmund C, Stern-Bach Y, Stevens CF. The tetrameric structure of a glutamate recep-
tor channel. Science. 1998;280(5369):1596-1599
[30] Pla SR. The role of glutamate in central nervous system health and disease—A review.
Veterinary Journal. 2007;173(2):278-286
[31] Evans AJ, Gurung S, Henley JM, Nakamura Y, Wilkinson KA. Exciting times: New
advances towards understanding the regulation and roles of kainate receptors. Neuro-
chemical Research. 2017 [Epub ahead of print]
[32] Niswender CM, Conn PJ. Metabotropic glutamate receptors: Physiology, pharmacol-
ogy, and disease. Annual Review of Pharmacology and Toxicology. 2010;50:295-322
[33] Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD. Metabotropic
glutamate receptors as novel targets for anxiety and stress disorders. Nature Reviews.
Drug Discovery. 2005;4(2):131-144
[34] Samardzic J, Svob Strac D. Benzodiazepines and Anxiety disorders: From laboratory to
clinic. In: Durbano F, editor. New Developments in Anxiety Disorders. Rijeka: InTech;
2016. pp. 23-45
[35] Jadzic D. Role of the Bed Nucleus of Stria Terminalis (BNST) in addiction and depres-
sion: a microdialysis study [PhD thesis]. University of Cagliari; 2018
[36] Car H, Wiśniewski K. Similarities and interactions between GABAergic and glutaminer-
gic systems. Roczniki Akademii Medycznej w Białymstoku. 1998;43:5-26
Introductory Chapter: GABA/Glutamate Balance: A Key for Normal Brain Functioning
http://dx.doi.org/10.5772/intechopen.74023
7