The role and the mechanism of gamma-aminobutyric acid during central nervous system development

Abstract

γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter in adult mammalian central nervous system (CNS). During CNS development,
the role of GABA is switched from an excitatory transmitter to an inhibitory transmitter, which is caused by an inhibition
of calcium influx into postsynaptic neuron derived from release of GABA. The switch is influenced by the neuronal chloride
concentration. When the neuronal chloride concentration is at a high level, GABA acts as an excitatory neurotransmitter. When
neuronal chloride concentration decreases to some degree, GABA acts as an inhibitory neurotransmitter. The neuronal chloride
concentration is increased by Na+-K+-Cl−-Cl− cotransporters 1 (NKCC1), and decreased by K+-Cl− cotransporter 2 (KCC2).

Full text

195
Neurosci Bull June 1, 2008, 24(3): 195-200. http://www.neurosci.cn
DOI: 10.1007/s12264-008-0109-3
·Minireview·
The role and the mechanism of γ-aminobutyric acid during central nervous
system development
Ke LI, En XU
Institute of Neurosciences, the Second Affiliated Hospital of Guangzhou Medical College, Guangzhou 510260, China
Abstract: γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter in adult mammalian central nervous system (CNS).
Corresponding author: En XU
Tel: 86-020-34152235
E-mail: enxu@tom.com
Article ID: 1673-7067(2008)03-0195-06
CLC number: R338.1
Document code: A
Received date: 2008-01-09
During CNS development, the role of GABA is switched from an excitatory transmitter to an inhibitory transmitter, which is
caused by an inhibition of calcium influx into postsynaptic neuron derived from release of GABA. The switch is influenced by
the neuronal chloride concentration. When the neuronal chloride concentration is at a high level, GABA acts as an excitatory
neurotransmitter. When neuronal chloride concentration decreases to some degree, GABA acts as an inhibitory neurotransmitter.
The neuronal chloride concentration is increased by Na
+
-K
+
-Cl
-
-Cl
-
cotransporters 1 (NKCC1), and decreased by K
+
-Cl
-
cotransporter 2 (KCC2).
Keywords: GABA; neurotransmitter receptor; central nervous system; development
1 Introduction
Amino acid, including glutamate, aspartic acid, γ-
aminobutyric acid (GABA) and glycine, is the major neu-
rotransmitter in the central nervous system. Glutamate and
aspartic acid are excitatory neurotransmitters. GABA and gly-
cine are inhibitory neurotransmitters. Excitatory neurotrans-
mitters act at postsynaptic receptors and presynaptic receptors,
which induce influx of Ca
2+
into neuron, as a result of en-
hancing the excitability of neuron. On the contrary, inhibi-
tory neurotransmitters inhibit Ca
2+
influx into neuron, weak-
ening the excitability of neuron. Glutamate and GABA play
an important role in enhancing and weakening the excitabil-
ity of neuron respectively.
It had been known for a long time that GABA is the
major inhibitory neurotransmitter in the mammalian central
nervous system (CNS); however, recently a lot of studies
have approved that the releasing of GABA in the early devel-
opment of CNS can increase the Ca
2+
concentration of
postsynaptic neuron, and then induce the depolarization of
postsynaptic neuron. GABA performs an excitatory function
during the early period of CNS development
[1,2]
.
This review focuses on the role that GABA plays in the
different period of CNS development. Both the change of
GABA in the different period of CNS development and the
underlying mechanism will be discussed.
2 GABA and its receptors in the adult mammal
CNS
GABA is one of the non-protein amino acids, which
means GABA is not a common amino acid to compose pro-
tein but a functional amino acid. GABA is the most represen-
tative inhibitory neurotransmitter in the adult CNS, which
distributes diffusely and nonuniformly in the mammalian CNS.
In the brain, there are about 25%-40% of the synapses that
use GABA as neurotransmitter, while only a very small
amount of GABA is found in peripheral nervous system.
GABA is synthesized principally with decarboxylation of
glutamate by glutamate decarboxylase (GAD) which requires
the cofactor pyridoxal 5’-phosphate (pyridoxal-P) for activity.
When GABAergic neuron is active, GABA is released from
nerve terminal to synaptic cleft and binds to receptors of GABA
in the postsynaptic membrane, acting as a neurotransmitter.

196
Neurosci Bull June 1, 2008, 24(3): 195-200
The unbound GABA is reuptaken to the neuron and gliocyte
by Na
-
/Cl
-
dependent GABA transporter, and is degradated
as a result of catalyzing into succinic semialdehyde (SSA) by
GABA transaminase (GABA-T)
[3]
.
The receptors of GABA can be divided into 3 subtypes:
GABA
A
receptors, GABA
B
receptors and GABA
C
receptors.
GABA
A
receptors are ligand-gated chloride ionotropic
receptors, which are the most principal receptors in
GABAergic synaptic transmission. When GABA
A
receptors
in the postsynaptic membrane are activated, the ion channel
of Cl
-
opens up and Cl
-
influx into the cells with lower density
Cl
-
through electrochemical gradient, which causes the hyper-
polarization of postsynaptic membrane; consequently inhibi-
tory postsynaptic potential (IPSP) is induced and the influx
of Ca
2+
is inhibited with the decrease of excitability of neuron
as a result. Wu YM et al.
found that the neuronal activity
could be inhibited by potentiating GABA
A
receptor-medi-
ated Cl
-
current in hippocampal CA1 neurons
[4]
. GABA
B
re-
ceptors are G protein coupled receptors, which have lower
concentration than GABA
A
receptors in CNS, and begin to
react in the late development of CNS (the beginning in ro-
dents is after birth)
[5]
. When GABA
B
receptors bind to GABA,
the coupled G protein are activated and the ion channel of K
+
opens up. The efflux of K
+
hyperpolarizes the postsynaptic
membrane, inhibits the influx of Ca
2+
, causing the
postsynaptic inhibition. GABA can also inhibit the releasing
of excitatory amino acid by binding GABA
B
-receptors of pre-
synaptic membrane and result in a presynaptic inhibition.
GABAc receptors are ligand-gated chloride ionotropic
receptors, which are different from GABA
A
receptors and only
exist in visual pathway.
3 GABA and its receptors in the early development
of CNS
Lin found that the Ca
2+
concentration of newly born
(postnatal days 0-5, P0-5) rat cortex neuron can be increased
dramatically by being perfused with GABA, and the neuron
of P0-2 had the largest extent in increase
[1]
. Ganguly con-
firmed in advance that using GABA to culture rat hippocam-
pus neuron of P4-9 results in a quick and reversibly enhanced
influx of Ca
2+
. The rat hippocampus neuron of P4-6 showed
an enhancement of GABA induced depolarization, however,
the rat hippocampus neuron of P13 showed no difference
[2]
.
This kind of Ca
2+
influx increasing can be blocked by GABA
A
receptors antagonist bicuclline or L-type Ca
2+
channel an-
tagonist nimodipine, nevertheless, it can not be blocked by
GABA
B
receptors antagonist baclofen, which clearly indi-
cates that the increased Ca
2+
influx is the result of the open-
ing of L-type Ca
2+
channel activated by the depolarization
with GABA
A
receptors.
All the studies mentioned above indicate that in early
stage of CNS development GABA raises the intracellular Ca
2+
concentration of postsynaptic neuron via GABA
A
receptors
and acts as an excitatory transmitter. With the developing
progress going, the extent of intracellular Ca
2+
concentration
increasing decreases gradually and the role of GABA switches
from excitatory transmitter to inhibitory transmitter. The
switches can be reversed easily by various factors. That is
why the nervous system in neonates is extremely vulnerable
to various etiological factors and frequently subject to the
damage.
4 The role of GABA changing from excitatory
neurotransmitter to inhibitory neurotransmitter
In the early stage of CNS development, GABA acts as
an excitatory transmitter. As the research kept moving on,
the mechanism of this phenomenon begin to attract the
researchers’ attentions. During the development of CNS,
GABA
A
receptors emerge earlier than GABA
B
receptors and
GABA
C
receptors and distribute more widely, so that most of
the GABAergic synaptic transmission is mediated via GABA
A
receptors. Because GABA
A
receptors are ligand-gated Cl
-
ionotropic receptors, so it is presumed that the role of GABA
switching is correlated with the concentration of intracellular
Cl
-
. In early development, the GABAergic reversal potential
(E
GABA
) is more liable to depolarize than resting membrane
potential, indicating that in the prenatal and early postnatal
days the concentration of intracellular Cl
-
is higher than
extracellular Cl
-
concentration
[6]
. When GABA
A
receptors
in the postsynaptic membrane are activated, the ion channel
of Cl
-
opens up and Cl
-
effluxes through electrochemical
gradient, and postsynaptic membrane is depolarized, facili-
tating the Ca
2+
influxes of postsynaptic neuron
[7]
. Following
the development, the intracellular Cl
-
concentration decreases
gradually. When the intracellular Cl
-
concentration is lower
than extracellular Cl
-
concentration, the role of GABA switch-
ing ends
[8]
. In adult mammal CNS, the intracellular Cl
-
con-
centration is lower than extracellular Cl
-
concentration. When

197
Ke LI, et al. Role of GABA during CNS development
GABA binds to GABA
A
receptors, the ion channel of Cl
-
opens and Cl
-
influxes through the electrochemical gradient,
and postsynaptic membrane is hyperpolarized, resulting in
the inhibition of the Ca
2+
influx of postsynaptic neuron, which
indicates that in the whole process GABA acts as a inhibi-
tory neurotransmitter
[9]
.
Further study found that the dominant factor respon-
sible for the significant change of intracellular Cl
-
concentra-
tion is cation-chloride cotransporter. To date, seven mem-
bers of the cation-chloride cotransporters gene family have
been reported, and they are designated by their ion selectivity
as KCC (KCC1-4) for K
+
dependent Cl
-
cotransporters, NCC
for Na
+
dependent or NKCC (NKCC1 and NKCC2) for
cotransporters that depend on the transmembrane gradients
of Na
+
and K
+
. Table 1 summarizes the key similarities and
differences among these cation-chloride cotransporters.
4.1 NKCC1 The cation-chloride cotransporters transport
Cl
-
into cell, including Na
+
-K
+
-Cl
-
-Cl
-
cotransporters (NKCC)
and Na
+
-Cl
-
-Cl
-
cotransporters (NCC). NKCC maintains intra-
cellular chloride concentration at levels above the predicted
electrochemical equilibrium, which is used by epithelial tis-
sues to promote net salt transport and by neural cells to set
synaptic potentials. Two isoforms of the NKCC are currently
known: NKCC1 and NKCC2. NKCC1, the “housekeeping”
isoform, exists in the brain and other systems, and its expres-
sion changes as it develops. NKCC2 seems to be exclusively
expressed in the kidney and mainly related with the urine
concentration by mediating apical Na
+
, K
+
and Cl
-
entry into
renal epithelial cells
[10]
. The NKCC1 isoform is the larger one
with 1 200 amino acid residues and a transcript size of 7.4 kb.
It has an overall 58% amino acid identity with NKCC2. The
NKCC2 isoform is somewhat smaller than NKCC1, contain-
ing 1 100 amino acid residues with a transcript size of 5 kb.
The difference in molecular size is almost entirely by an addi-
tional 80 amino acids at the amino terminus of the NKCC1.
NCC is a Na
+
-Cl
-
-Cl
-
cotransporter, which also increases the
intracellular Cl
-
concentration
[11]
.
There are several factors to control the operation of
NKCC, including ATP, intracellular ions and cytoskeleton.
ATP plays a fundamental role in the operation of the NKCC.
The majority of available evidence supports the present view
that the effects of ATP on the NKCC are mediated via a pro-
tein phosphorylation/dephosphorylation mechanism
[12]
.
Nevertheless, the NKCC is an example of secondary active
transport that derives it energy from the combined chemical
gradients of the three cotransported ions. So the change of
intracellular ions concentrations is the most critical factor.
Furthermore, the changes of cell volume will be “sensed” by
the cytoskeleton. In turn, the resultant cytoskeletal changes
will be transmitted to the membrane ion transporters in the
plasmalemma through the cortical cytoskeletal network of
actin and associated proteins.
Tab. 1 Comparison of general properties of NKCC, KCC and NCC
Property NKCC KCC NCC
Cotransport ions Na
+
, K
+
, Cl
-
K
+
, Cl
-
Na
+
, Cl
-
Direction of net cotransport Influx Efflux Influx
Loop diuretic sensitive Bumetanide > furosemide Furosemide > bumetanide No effect
Thiazide sensitive No effect ? No effect
Isoforms: tissue distribution NKCC1: KCC1: Urinary bladder,
kidney, stomach, brain, colon, distal convoluted tubule
heart, lung, brain, heart, kidney,
skeletal muscle liver, lung,
NKCC2: spleen, stomach
kidney KCC2:
brain
Effects of inhibiting intracellular Cl
-
Inhibit Stimulate ?
Electrically silent Yes Yes Yes

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In the internally dialyzed squid giant axon, elevation
of [Cl
-
]
i
inhibits the unidirectional fluxes of all three
cotransported ions in both the influx and efflux
[13]
. These
findings grew out of an early observation that the removal of
intracellular Cl
-
had the surprising effect of increasing Cl
-
influx. Since then, the role of NKCC1 on the intracellular Cl
-
concentration began to be recognized. So it was postulated
that immature neurons depolarize in response to GABA
A
re-
ceptor activation as a consequence of active Cl
-
accumula-
tion via NKCC1. By using in situ hybridization technology,
Clayton found that only NKCC1, instead of NKCC2 and NCC,
exists in the brain, and the expression of NKCC1 reaches the
highest level at the third postnatal weeks, then decreases
significantly, and stays at low level until adult
[14]
. Indeed,
NKCC1 transcripts were detected in the developing CNS as
early as embryonal day 12.5, when expression was observed
in scattered cells of the neuroepithelium
[15]
. By studying in
Wistar rats at postnatal 1-21 d, Yamada found that in the
early CNS development, the expression of NKCC1 mRNA is
much higher than that in the later development, with the ex-
pression at the highest level in Wistar rats at postnatal 0-3 d
[16]
.
The functional importance of NKCC1 in GABA signaling has
been showed by targeted deletion
[17]
.
It is clear that only NKCC1 exists in the immature brain
and there is robust expression of NKCC1 in immature neurons,
with subsequent downregulation in mature neurons, which
is correlated with the role change of GABA. Moreover, the
antagonist of NKCC1 can inhibit the excitatory activity of
GABA by decreasing the intracellular Cl
-
concentration.
Dzhala VI made substantial findings by researching into rats
at postnatal 6-23 d
[18]
. The NKCC1 antagonist bumetanide
can control the seizure of rats at postnatal 6-12 d, but the
traditional anti-epileptic drug phenobarbital can not; Phe-
nobarbital can control the seizure of rats at postnatal 21-23 d,
but bumetanide is invalid. The generation of epilepsy is re-
lated with the unbalanced releasing of excitatory neurotrans-
mitters and inhibitory neurotransmitters. The traditional anti-
epileptic drugs inhibit the postsynaptic Ca
2+
influx by imitat-
ing the inhibitory activity of GABA and increasing the intra-
cellular Cl
-
concentration. The Cl
-
concentration of neonatal
mammal CNS is higher than the extracellular Cl
-
concentration.
When the GABA
A
receptors are activated by traditional anti-
epileptic drugs, the postsynaptic neuron Cl
-
effluxes and Ca
2+
influxes, which leads to the increase of neuronal excitability.
That is why the traditional anti-epileptic drug phenobarbital
can not control the seizure of rats at postnatal 6-12 d. The
NKCC1 antagonist bumetanide controls the seizure of neo-
nate by decreasing the intracellular Cl
-
concentration and
inhibiting the excitatory activity of GABA. It indicates that
intracellular Cl
-
concentration is at high level during the pe-
riod of postnatal 6-12 d, when GABA acts as an excitatory
neurotransmitter, and the intracellular Cl
-
concentration is at
low level during the period of postnatal 21-23 d, when GABA
acts as an inhibitory neurotransmitter. NKCC1 has an influ-
ence on the transition process.
Obviously, in the early development of CNS, the high
concentration of intracellular Cl
-
is mainly caused by NKCC1,
and with the development, the decreased expression results
in the intracellular Cl
-
concentration reduced to lower level to
some degree.
4.2 KCC2 KCC is one of the superfamily of cation-chloride
cotransporter, and cotransports K
+
and Cl
-
out of the cell
through the electrochemical gradient of K
+
, which decreases
the intracellular Cl
-
concentration. KCC family includes KCC1,
KCC2, KCC3 and KCC4. KCC2 only exists in the nervous
system and is the only one who can cotransport K
+
and Cl
-
under isotonic conditions
[19]
. KCC2 increases the rate of Cl
-
extrusion, thus leading to a reduction of [Cl
-
]
i
and a conse-
quent negative shift in E
GABA
. Indeed, Li has already found
that the change in the KCC2 mRNA level correlates with the
ontogenic switch in GABAergic transmission from depolar-
ization to hyperlarization
[20]
. Furthermore, Clayton found that
KCC2 expressed prenatally at very low levels which increased
dramatically after the first week of postnatal life
[14]
. Thus, the
expression level of the neuronal-specific K
+
-Cl
-
cotransporter
KCC2 is a major determinant of whether neurons will respond
to GABA with a depolarizing, excitatory response or a
hyperpolarizing, inhibitory response.
When the expression of KCC2 is at a lower level, GABA
tends to play the excitatory role. Some researchers presumed
that the down regulation of KCC2 resulted in role switch of
GABA, which is the reason for the hypoxia induced seizure.
It has already found that the mutation of K
+
/Cl
-
cotransporter
gene kazachoc can increase seizure susceptibility of flies
[21]
.
Mercado found that the expression inhibition of KCC2 can
lead to the death of the neonatal rats for epileptic seizure
[22]
.
During the development of nervous system, the expres-
sion of KCC2 increases gradually. Upon the birth of a rat,

199
Ke LI, et al. Role of GABA during CNS development
KCC2 barely expresses in the brain stem. KCC2 expresses in
the hippocamp us about a week after birth, and expresses in
the cortex between 1-2 weeks after birth
[23]
. At present, it is
figured that the inducing factor of KCC2 expression is GABA
itself. Ganguly found that GABA
A
receptors antagonist
bicuculline and picrotoxin can noticeably inhibit the expres-
sion of KCC2 mRNA, and the antagonist of glutamate recep-
tors showed no effect to the expression of KCC2 mRNA
[2]
.
Those results indicate that GABA, as a signal, activates the
intracellular cascade for KCC2 expression regulation. That is
how GABA changes its role in the synaptic transmission by
controlling the intracellular Cl
-
concentration indirectly.
But the absence of expression of the known Cl
-
cotransporters in neuroepithelium and glia suggests that
other as yet unidentified members of this gene family may be
involved in chloride homeostasis in immature neuronal pre-
cursors and neuroglia.
5 Conclusion
In the CNS development, GABA changes from an exci-
tatory neurotransmitter in the early phase to an inhibitory
transmitter in the maturation phase. The main reason for the
role switch of GABA is the expression change of cation/
chloride cotransporter NKCC1 and KCC2. More investiga-
tion into the mechanism of the expression change of NKCC1
and KCC2 in the CNS development is needed in further study.
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Neurosci Bull June 1, 2008, 24(3): 195-200
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γ - 氨基丁酸在中枢神经系统发育中的作用及机制
李珂，徐恩
广州医学院第二附属医院神经科学研究所，广州 510260
摘要：γ-氨基丁酸 (γ-Aminobutyric acid, GABA) 是成年哺乳动物中枢神经系统内的抑制性神经递质。在中枢神经系
统发育过程中，GABA 由兴奋性神经递质转变为抑制性神经递质。其转变过程主要表现为 GABA 的释放由促进突
触后神经元的Ca
2+
内流变为抑制突触后神经元的Ca
2+
内流。中枢神经元内GABA作用的转变受细胞内Cl
-
浓度的影
响：当细胞内Cl
-
浓度处于高水平时GABA发挥兴奋性神经递质的作用，当细胞内Cl
-
浓度降低到一定程度后GABA
发挥抑制性神经递质的作用。升高中枢神经元内 Cl
-
浓度的是 Na
+
-K
+
-Cl
-
-Cl
-
同向转运蛋白 1 (Na
+
-K
+
-Cl
-
-Cl
-
cotransporters 1, NKCC1)，而 K
+
-Cl
-
协同转运蛋白 2 (K
+
-Cl
-
cotransporter 2, KCC2）则使中枢神经元内 Cl
-
浓度降低。
关键词：γ- 氨基丁酸；神经递质受体；中枢神经系统；发育
GABAergic signalling: the K
+
-Cl
-
cotransporter KCC2 and car-
bonic anhydrase CAVII. J Physiol 2005, 562: 27-36.