Hindawi Publishing Corporation
Volume 2011, Article ID 527605, 16 pages
AlteredGABA SignalinginEarly LifeEpilepsies
Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine,
1410 Pelham Parkway South, Kennedy Center Rm 306, Bronx, NY 10461, USA
Correspondence should be addressed to Aristea S. Galanopoulou, firstname.lastname@example.org
Received 7 February 2011; Revised 4 May 2011; Accepted 27 May 2011
Academic Editor: Laura Cancedda
Copyright © 2011 S. W. Briggs and A. S. Galanopoulou. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during
normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been
speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABAAsignaling by reshuffling
the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABAAreceptor
and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often
effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have
explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal
seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and
sex-appropriate development of the brain.
episodes of aberrant synchronous excitation of brain regions
that disrupt normal functioning [1, 2]. Epileptic seizures are
thought to reflect a failure in the ability to maintain the
balance between excitation and inhibition. The mechanisms
underlying seizures are complex and not uniform across
the numerous seizure types that exist . Furthermore, our
we can use: we can only see as far and as much as those
the pathogenesis of seizures are biased by the dominant ictal
phenomena, unbalanced excitation-inhibition and aberrant
neuronal synchronization, which may not necessarily be the
actual ictogenic mechanisms. Neurotransmitters involved in
neuronal inhibition, such as GABA, have attracted the major
focus of research aiming to decipher mechanisms involved
in ictogenesis. Under certain conditions, and definitely not
in the majority of cases, seizures may lead to epilepsy
or neurodevelopmental deficits. The early periods of life,
when brain development is still incomplete, susceptibility
to seizures is increased [3, 4]. However, a combination of
biological factors (genetic, age-related processes, epigenetic
or environmental factors) protect neurons from seizure-
induced injury, epileptogenesis, or mortality to a greater
extent than the adult brain is protected . It is increasingly
recognized that seizures may leave their imprint on the
developing brain by altering the way that neurons differen-
tiate, connect, and communicate to each other, even if, in
many cases, such changes may be ultimately compensated
for. As extensively outlined in the reviews included within
this special issue, GABA plays a central role in controlling
neuronal development and communications. A major focus
its role not only in ictogenesis but also in the pathogenesis
of the sequelae of early life seizures, whether this may be
epilepsy, cognitive, or behavioral deficits .
There are three types of GABA receptors reported in the
literature: GABAA, GABAB, and GABAC, the latter classified
more recently along with GABAA receptors, due to their
functional similarities. Both GABAAand GABACreceptors
are ligand-gated ionotropic channels that allow primarily
chloride but also bicarbonate to cross their pore in response
to GABA binding. GABAB is a metabotropic receptor that
signals through cascades that modify potassium and calcium
current (reviewed in ), direct migration , and control
gene transcription [9, 10]. In this review, we will focus
primarily on GABAAreceptors.
GABAAreceptors are pentameric channels usually com-
prised of 2α and 2β subunits, whereas the fifth is either a
γ or a δ subunit. Less frequently, ε, θ, or π subunits are
present [11–13]. There are 16 known mammalian GABAA
receptor subunits (α1 − α6,β1 − β3,γ1 − γ3,δ,ε,θ,π),
which contribute towards the different pharmacokinetic,
subcellular localization or affinity properties of each GABAA
receptor complex. The presence of a ρ subunit defines the
GABAC receptors. Unlike GABAA receptors, GABAC are
insensitive to bicuculline. The expression of GABAAreceptor
subunits changes with development and as a result the
responsiveness of immature and adult neurons to GABAA
ergic modulators are significantly different.
The classical inhibitory GABAA signaling, as occurs
in most adult neurons, is due to chloride influx through
the channel pore, which hyperpolarizes the cells. This is
achieved because the intracellular chloride concentration
is maintained at a low level, allowing chloride to flow in
along its electrochemical gradient, when GABAA receptors
open (Figure 1). Multiple studies over the last few decades
have confirmed that this electrochemical chloride gradient
is developmentally regulated by changes in the expression of
cation-chloride cotransporters (CCCs). CCCs are the elec-
between cells and their extracellular environment. There are
3 CCC classes. The chloride importing CCCs are either the
sodium/potassium/chloride cotransporters (NKCCs), with
known representatives the NKCC1 and NKCC2, or the
sodium chloride cotransporters (NCCs). Chloride exporters
are the potassium/chloride cotransporters (KCCs), with
4 known isoforms: KCC1-4 (reviewed in [11, 12, 14,
15]) (Figure 1). Immature neurons express predominantly
chloride-importers, such as NKCC1 , which generate
high intracellular Cl−levels. This forces the open GABAA
receptors to permit Cl−efflux through their channel pore,
giving rise to depolarizing GABAAresponses [16–18]. Dur-
ing developmental maturation, the expression of chloride-
extruding CCCs, like the potassium/chloride cotransporter
2 (KCC2), dominates over NKCCs [19–22], decreasing
the intracellular chloride concentration . As a result,
when GABA opens GABAAreceptors the ensuing influx of
chloride results in hyperpolarizing currents  (Figure 1).
However, cell type, sex, and species/strain differences occur
in the timing of this developmental shift. KCC1, KCC3
and KCC4 are widely expressed, but KCC2 is specific to
neurons. This makes KCC2 particularly interesting for the
pathogenesis and therapy of neural diseases. NKCC2 expres-
sion is specific to the kidney, leaving NKCC1 as the most
relevant chloride-importing cotransporter for the brain,
though it is expressed ubiquitously. Bicarbonate, generated
can permeate the GABAAreceptor, generating a depolarizing
response [12, 24, 25]. The cytosolic carbonic anhydrase
VII (CAVII) increases around postnatal day 12 (PN12) in
the rat hippocampus , rendering bicarbonate-mediated
GABAAdepolarizations more prominent .
There is considerable evidence that alterations in GABA
signaling can cause seizures, as well as that seizures can
change GABAergic signaling. In this review, we will discuss
the bidirectional relationship of seizures to GABAAsignaling
at the level of the neurons, GABAA receptors, and the
ionic symporters that control chloride homeostasis and the
efficiency of GABAAreceptor mediated inhibition.
2.Correspondence of Developmental Stages
betweenRodents and Humans
To facilitate the translation of the experimental data into
humans, it is worth reminding that the accepted correspon-
dence of developmental stages between rodents and humans
considers that the first week of life in rodents is equivalent to
a premature newborn human, whereas the time of birth in
rodents is considered to correspond to PN8-10. The rodent
infantile stage is thought to extend till PN21, the onset of
puberty is at PN32-35 in rodents, whereas PN60 rodents
are considered young adults. However, it is important to
mostly on correspondence of protein and DNA content in
the brain. Each developmental process occurs at different
tempos and is not always in synchrony with the above
sequence of events. For example, by the end of the first
unlike the human newborns who cannot yet ambulate .
Direct demonstration of the time of shift of GABAAreceptor
responses to hyperpolarizing has not been demonstrated in
humans, though it has been suggested to occur before or
soon after birth, based on the developmental patterns of the
relative expression of NKCC1 and KCC2 [21, 28].
3.The Immaturityof GABAAergic Systemsas
anAge andSex-Specific Risk Factorfor Early
Seizures are more common in the early periods of life and
especially in males [3, 4]. The immaturity of GABAergic
inhibitory systems has been implicated in the heightened
susceptibility of neonates to seizures and may also underlie
of these systems is delayed compared to females. GABA is
depolarizing in the neonatal life and it stays depolarizing
for longer developmental periods in the male brain than
in females [17, 29–33]. Paradoxical exacerbation of seizures
by GABA-acting drugs has been reported in newborns,
especially in low weight premature babies . GABA-acting
drugs, such as benzodiazepines and barbiturates, however,
still remain the mainstay of treatments for neonatal seizures,
babies as in older patients [21, 35–39]. This is thought to
be due to shunting inhibition or inhibition via excitatory
effects upon inhibitory interneurons . The composition
Figure 1: CCCs control GABAAreceptor-mediated inhibition. Panels (a) and (b) show the effects of NKCC1 activity in the absence (panel
(a)) or presence (panel (b)) of GABA. NKCC1 mediates the electroneutral cotransport of Na+, K+, and 2 Cl−, increasing the intracellular
Cl−concentration. As a result, upon binding of GABA upon the GABAAreceptor, the channel pore opens and Cl leaves the neuron, causing
a depolarization. Panels c and d show the effects of NKCC1 activity on GABAAreceptor function in the absence (panel c) or presence (panel
d) of GABA. KCC2 in contrast exports K+and Cl−reducing intracellular Cl−. Activation of GABAAreceptors therefore results into influx
of Cl and hyperpolarizing current. Their function is dependent upon the gradients of Na+and K+, which are controlled by various factors,
including background conductances, membrane voltage, and by the Na+/K+ATPase.
of GABAAreceptors is also different in newborns, with less
α1 and more α2/3 subunits, rendering them less responsive
to benzodiazepines [41, 42]. Furthermore, the subcortical
46]. The excessive GABAergic stimulation of the SNR, as is
thought to occur due to GABA release during seizures, has
proconvulsant effects early in life and anticonvulsant in older
animals and this switch occurs earlier in females [44, 45].
It is therefore important to investigate and clarify the exact
molecular determinants that control GABAA inhibition in
the young brain so as to optimize the treatment of seizures.
Clinical and experimental evidences indicate that an initial
perturbation of GABAAsignaling may facilitate seizures. A
loss of inhibition could result in runaway excitatory circuits.
Too much inhibition could also cause a seizure, either
by disinhibiting epileptogenic networks or via promoting
neuronal synchronization ( reviewed by ). Excessive
inhibition has been implicated in autosomal dominant
nocturnal frontal lobe epilepsy (ADNFLE) (  reviewed in
is critical for brain development and early synaptogenesis
[72–74], a disorder of GABAA signaling early in life may
Many GABA-related mutations are known to cause early
life epilepsy. These include loss of function mutations or
deletions of GABAAreceptor subunit genes that reduce their
expression, or the duration, amplitude or agonist sensitivity
of GABAA currents. GABAA receptor subunit mutations
have been implicated in childhood absence epilepsy (CAE)
[50, 51, 75], autosomal dominant epilepsy with febrile
seizures plus (ADEFS+) , and other epileptic syndromes
cate that the developmental period of exposure to insults
that disrupt GABAAsignaling may be critical in ictogenesis
and epileptogenesis. Chiu et al. proposed that loss of func-
tion mutations of the GABAA receptor subunits may have
Table 1: GABA-related mutations linked with seizures.
GABA-related mutationsSpeciesEpilepsy type
Age at first
GABRA1Human ADJME, CAE
IGE, ADEFS+, Febrile
Early life epileptic
developmental effects in addition to their direct electrophys-
iological consequences . Using a conditionally expressed
loss of function mutation of the γ2 GABAAreceptor subunit
in mice, the investigators expressed the mutant allele for
different periods of time. Mice that were induced to express
the mutant allele for longer developmental periods displayed
higher seizure susceptibility to pentylenetetrazole (PTZ), a
drug that acts as a GABAAreceptor antagonist, compared to
mice with late disruption of the γ2 subunit expression.
Glutamic acid decarboxylase (GAD) isoforms GAD65
and GAD67 synthesize GABA in the brain. Knockout
mice for the pyridoxal-5?-phosphate inducible GAD65
isoform, that generates the GABA reserve pools, have
lower seizure threshold to picrotoxin, a GABAA receptor
antagonist , or spontaneous seizures that can be pre-
cipitated by stress . Although total GABA content
in the brain may be normal or decreased in GAD65
knockout mice, depending upon the genetic substrate, it
has been proposed that GAD65 loss of function may
preferentially decrease the presynaptic reserve pool of
GABA and decrease the tonic GABA inhibition, leading
to increased seizure susceptibility [80–82]. Although no
human GAD mutations have been found to consistently
cause epilepsy , mutations in co-factors that are nec-
essary for GAD65 function have been linked with early
life seizures, as occurs in pyridoxine-de-pendency disorders
[84, 85]. GAD65 or GAD67 loss suf-ficiently compensates
for each other and does not appear to affect early brain
development; albeit, cleft palate has been reported with
GAD67 knockout mice . Dual GAD65/67 knockout mice
are not viable . A small subset of patients manifests
epilepsy secondary to an autoimmune response against
GAD65/67, although these appear mostly in adults [88–
Decreased expression or function of chloride extruders may
change seizure susceptibility by not only diminishing the
and degeneration under hypotonic conditions, but also
by exerting broader developmental effects. Human linkage
studies or transgenic knockout animal studies document
that, at least in certain cases, seizures and epilepsy may
ensue. There is currently no known human mutation of
KCC2 associated with epilepsy. This may rather reflect
the indispensability of KCC2, as complete KCC2 knockout
mice die postnatally from respiratory failure, due to the
immaturity of the respiratory system . KCC2 has two
known isoforms, KCC2a and KCC2b, of which KCC2b
is thought to contribute to the developmental shift to
hyperpolarizing GABAA receptor currents . KCC2b-
knockout mice demonstrate hyperexcitability at PN10 to
PN16 (equivalent to human infantile age)  (Table 2).
and depolarizing shift of GABAA responses could easily
explain the hyperexcitability, application of the GABAA
receptor antagonist picrotoxin paradoxically retains its exci-
tatory responses . Similarly, a different hypomorphic
mutation in KCC2 causes a lower PTZ threshold for
induction of clonic seizures in mice, despite the absence
of gross morphological changes . Such observations are
Table 2: Phenotype of CCC mutations.
KCC2BrainMouseDeath at birth 
BrainHypomorph Mouse 
KCC4Kidney, heart, lungs, liver Knockout
indicative of a residual inhibitory capacity of KCC2, either
in the form of less potent hyperpolarizing GABAAreceptor
currents or shunting inhibition . However, the function
of KCC2 is more complex, due to interactions with dendritic
cytoskeletal proteins  or with other modulators of
neuronal activity (i.e., increasing extracellular potassium)
 which need to be further analyzed as to their ability
to influence the phenotype of these mice.
Loss of function mutations in KCC3, which is expressed
in many tissues, have been reported in patients with heredi-
tary motor sensory neuropathy, some of whom have seizures
as well as developmental deficits, like agenesis of the corpus
Altered CCCs may also affect brain development in a
more subtle fashion, which could predispose a brain to
epilepsy even if it does not directly cause seizures. From
various fronts evidence emerges that shifts in the tim-
ing of emergence of hyperpolarizing signaling may have
significant impact on neuronal and brain development
and connectivity. Precocious appearance of hyperpolarizing
GABAA receptor signaling, either by KCC2 overexpression
 or via loss of NKCC1 activity , disrupts cortical
morphogenesis. Pharmacological inhibition of NKCC1 with
bumetanide from embryonic day E15 to PN7 in otherwise
normal mice disrupts cortical dendritic formation .
Abnormal cortical development and synaptic connectivity
may predispose to seizures or cognitive impairment, which
is both a predisposing factor and a common comorbidity of
young patients with epilepsy .
6.Secondary Disruptionof GABAergic
SignalinginRisk Factorsfor EarlyLife
Conditions that predispose to epilepsy, genetic or acquired,
may also create an imbalance in excitation/inhibition.
Although their effects are not restricted to GABAAsignaling,
impair GABAergic inhibition.
Mutations of the aristaless-related and X-linked home-
obox gene ARX have attracted a lot of interest due to their
linkage with early life catastrophic epileptic syndromes, such
asinfantile spasms,Ohtaharasyndrome,X-linked myoclonic
seizures, spasticity and intellectual disability, idiopathic
infantile epileptic dyskinetic encephalopathy, X-linked men-
tal retardation [63–66, 112–116] (reviewed in ). ARX
is a transcription factor that regulates the proliferation and
Figure 2: Schematic depiction of simple models through which
dysregulation of GABAAreceptor-mediated inhibition can increase
the activity of neuronal networks, potentially generating seizures.
GABA inhibition can fail when GABA or GABAAreceptor expres-
sion is low, when GABA depolarizes neurons, or when miswiring
and mistargeting of synapses occur. Excessive GABA inhibition may
trigger seizures by disinhibiting target cells, or via excessive syn-
chronization of the neurons in the epileptogenic focus. Please note
that the effects of dysregulated GABA signaling in more complex
neuronal networks, especially in the presence of abnormal circuitry
or with specific pathologies, may differ. In such cases a combination
of the above models may be applicable at different sites of the
epileptogenic network rendering the pharmacological effect of a
GABAergic agonist not completely predictable by a single model.
Furthermore, shunting inhibition may explain situations where
GABAergic drugs silence excessive excitatory network activity, in
neurons with depolarizing GABAergic signaling.
migration of GABA, calbindin, or neuropeptide Y positive
interneurons but also of striatal cholinergic neurons [64, 66,
117]. Two recently published mouse models of ARX loss
of function mutations, one of which specifically disrupted
it in GABAergic interneurons destined to migrate to the
neocortex, have recapitulated several phenotypes of infantile
spasms and associated phenotype (cognitive, behavioral
deficits and epileptogenesis) emphasizing the importance of
deficient GABA inhibition for their pathogenesis [64, 66].
Angelman syndrome, a rare chromosomal deletion,
involves the loss of ubiquitin-protein ligase 3A (UBE3A),
but in certain patients there is a more extensive deletion of
the15q11-13 chromosomallocus thatcontains threeGABAA
subunits, α5, β3, and γ3 GABAA receptor subunits .
Genotype-phenotype correlation suggested that deletion of
the GABAAreceptor subunits is associated with more severe
seizures, including infantile spasms, atypical absences, and
myoclonus whereas patients with UBE3A mutations had a
milder phenotype . The β3 subunit knockout mouse
strain also develops a similar epilepsy phenotype .
Loss of function mutations of the voltage-sensitive
sodium channel SCN1A gene is found in not only the se-
vere myoclonic epilepsy of infancy (Dravet syndrome) but
also in ADEFS+syndrome [120–123]. SCN1A mutations
have been proposed to preferentially impair the sodium
channel activity of GABAergic interneurons, diminishing
their activity . Anti-NMDA autoantibodies detected in
limbic encephalitis, a rare cause of refractory and frequent
seizures , have been speculated to selectively target
the NMDA receptors of presynaptic GABAergic terminals,
reducing therefore GABA release .
Aberrant reappearance of depolarizing EGABA and
reduced GABAAergic responses have been proposed to
underlie the pathogenesis of seizures from cortical malfor-
mations. Pathology and electrophysiological studies from
human tissue specimens from patients with cortical dys-
plasias, that commonly predispose to early life seizures, have
also suggested the presence of depolarizing GABA [20, 127,
128]. In the neonatal freeze lesion model, a shift to the
immature pattern of high NKCC1/KCC2 ratio in the lesional
site  as well as reduced γ2 subunit expression and
sensitivity to α1 subunit agonists in adulthood was described
[130, 131]. In the rat model of cortical dysplasias induced
by prenatal exposure to the 1-3-bis-chloroethyl-nitrosurea,
reduced sensitivity to GABA was also seen in adulthood
Traumatic brain injury in adults, such as in axotomized
neurons, causes a reversal of GABAA signaling and CCC
expression profile to the immature pattern (more depo-
larizing GABA and dominant NKCC1 over KCC2 activity)
[133–135]. This appears to aid the survival and regeneration
process, promoting the brain-derived neurotrophic factor-
(BDNF-) dependent neuronal survival and may resolve
with time, during recovery . However, there is limited
the expression, physiology, and connectivity of GABAergic
interneurons in developing animals. In the partially iso-
lated undercut cortical model, reduced GABAAergic IPSCs
and impaired chloride extrusion were found in juvenile
rats, suggesting a possible correlation between impaired
GABAergic inhibition and posttraumatic cortical excitability
[136, 137]. Few studies have advocated against the use of
GABA enhancing drugs and in favor of GABAA receptor
inhibitors as interventions to improve cognitive outcomes
. More detailed studies are needed to determine the role
of posttraumatic GABAAsignaling changes for healing and
regeneration in the developing brain as well as its impact on
subsequent epileptogenesis and ensuing cognitive deficits.
Seizures can affect almost every neurotransmitter system in
the brain. Seizures can have immediate effects on GABAA
signaling, that is, during the ictal period, or delayed, appear-
ing after the termination of seizures. In both scenarios, the
observed changes are dynamic and evolving. Seizures may
interfere with the expression, composition, and subcellular
such as CCCs or regulatory kinases. Defining the timing of
these events is crucial, not only to better understand the
pathophysiological mechanisms investigating these changes
but also to best interpret their pathophysiological rele-
vance for epileptogenesis and brain function. The temporal
Table 3: Effects of early life seizures on GABAAreceptors and currents in rats.
Seizure model AgeRegion
Effects on GABAA
In vivo SE
expression of β2/3, γ2
subunits but not of δ.
In vivo SE
4–7 week old Hippocampus
Internalization of β2/3,
γ2 subunits; reduced
Decreased amplitude of
Flurothyl seizures PN6 or PN6-10Hippocampus
Decreased numbers of
At 3 weeks postictally:
α2, α3 increase;
α5 increase (CA3 only);
β3 increase compared to
In adulthood: increased
α1 expression, larger
Decreased α1 and
increased α4 expression
in the hippocampus of
Kainic acid SEPN9 Hippocampus
evolution of these events is also particularly important in
developing rats, given the maturational changes that are
ongoing. In addition, the age at first seizure, the type and
severity of seizures, sex, epigenetic factors, medications, but
further modify the final outcomes.
The urgency in treating early SE has long been recognized
in the clinical literature. GABA-acting drugs, like benzodi-
azepines or barbiturates, are more effective early at onset
of seizures than later on, when SE has been established
[147, 148]. The transience of the efficacy of GABAergic
selective synaptic GABAAreceptor subunits, such as of β2/3
and γ2, which mediate the effects of benzodiazepines and
barbiturates [139, 140]. On the other hand, extrasynaptically
located subunits that mediate tonic GABA inhibition, like
the δ subunit, are not affected . Failure of GABAA
receptor-mediated inhibition during prolonged seizures may
also occur due to a positive shift in EGABA either because
of buildup of intracellular Cl−concentration, from intense
GABAA receptor-mediated chloride inward pumping, or
from impaired chloride extrusion mechanisms, due to
increased NKCC1 activity or decreased KCC2-mediated Cl−
7.2. Postictal Changes. Loss of GABAergic interneurons is a
hallmark pathology of focal epilepsies, like mesial temporal
sclerosis [152–157]. In experimental studies, prolonged
seizures can lead to interneuronal loss but such effects
are age-specific. In newborn rats, during the first week
of life, even 3 episodes of status epilepticus (SE) do not
injure GABAergic neurons ; yet cell death becomes a
progressively more prominent feature as the age at exposure
to SE increases [155, 158–160]. In contrast, early life seizures
functionally disrupt the physiology of GABAA receptor
system. Age at the time of seizures, etiology or model
of seizures, biological factors such as sex, as well as cell
type and region-specific features may determine the end
effects upon GABAA receptor subunits or the direction of
GABAAreceptor-mediated responses (Tables 3 and 4). These
changes may be either compensatory attempts to repair or
restore normal function or, on the contrary, may contribute
Table 4: Effects of Seizures on CCCs.
Rat PN6-7 Hippocampus
(at least 4 days
No change in
shift of EGABA
(at least 4 days
to the postictal dysfunction, comorbidities, or sequelae of
seizures, such as cognitive dysfunction or epileptogenesis.
Unlike the adults, in which the physiology of GABAA
receptor-mediated signaling has reached a relative steady
state, developmental research is further complicated by the
evolving changes that normally occur during the period
when brain matures. There is no systematic research
study taking us step-by-step through all the complexity
of seizure-induced postictal alterations in GABAAreceptor
physiology and anyextrapolations should be cautiouslydone
pending confirmation by actual experimentations.
Seizures selectively interfere with the expression of
certain, but not all, GABAA receptor subunits [141–146]
(Table 3). Kainic acid SE at PN9 rats favors the preservation
of the immature pattern of GABAAreceptor complex (less
α1, more α2/α3 subunits) on the third postictal week
 that typically attributes slower IPSC kinetics and less
sensitivity to benzodiazepines. Similarly, recurrent flurothyl-
induced seizures, in the first 10 days of life, decrease α1
expression and the amplitude of GABAAreceptor-mediated
IPSCs [141–143]. Looking at longer-term outcomes of early
life seizures, during adulthood, Brooks-Kayal’s group has
demonstrated that age at onset of SE is key at defining the
final composition of GABAAreceptors and that this, in turn,
PN10 increases α1 subunit expression in the dentate granule
cells in adulthood; in contrast, if SE is induced at PN20, a
decrease in α1 subunit is noted, but only in the epileptic ani-
mals [145, 146]. Interestingly, reconstitution of α1 subunit
expression prevented the occurrence of spontaneous seizures
The reports of untimely appearance of depolarizing
GABAA receptor signaling in a subpopulation of subicular
neurons from adult human epileptic resected temporal lobes
have attracted a lot of interest as a possible mechanism of
epileptogenicity and potential refractoriness to GABA-acting
antiepileptics [163, 164]. Depolarizing GABAA receptor
signaling has been linked to a dominance of NKCC1 over
KCC2 activity in certain neurons of the epileptic tissue. It
may also occur because of effective replenishment of intra-
cellular bicarbonate by carbonic anhydrase during intense
GABAAreceptor activation, which leads to a depolarization
and to a consequent influx of Cl−, that enhances KCC2-
mediated K+/Cl−efflux . The sequential interaction
between carbonic anhydrase/GABAA receptors/KCC2 may
therefore increase extracellular K+, a factor that promotes
inhibitors have been used in certain cases as anticonvulsant
therapies [109, 165].
Seizures in adult animals tend to increase the ratio of
NKCC1 over KCC2 activity, reverting to a more immature
pattern of CCC balance that favors depolarizing EGABA[151,
166]. This is believed to occur in humans as well [127, 167–
170]. But what happens, then, after early life seizures, when
neurons are already in an immature state and how does
this impact epileptogenesis and functional outcomes? In the
immediate postictal period, following brief recurrent kainic
acid seizures or an hour of kainic acid SE, KCC2 is reshuffled
towards the plasma membrane, increasing its capacity to
export Cl−. As a result EGABAbecomes more negative,
contributing perhaps to the ability of the neurons to stop
In the longer run, further changes in EGABA function
occur, which are attributed to altered CCC expression or
activity . In our lab, we were interested in determining
whether the original EGABA, at the time seizures occur, may
control the effects of seizures on CCCs and the direction
of GABAA receptor-mediated signaling, in other words,
whether seizures might have different effects upon GABAA
receptor-mediated signaling in neurons with depolarizing
or hyperpolarizing GABAA receptor mediated responses at
the time of seizures. Taking advantage from the earlier
appearance of GABAA receptor currents in females than
in males, we compared the effects of 3 episodes of kainic
acid SE elicited at PN4, 5, and 6 (3KA-SE) in CA1
pyramidal neurons with depolarizing EGABA (i.e., male)
or isoelectric/hyperpolarizing EGABA (i.e., female) at the
time of seizures . We found that 3KA-SE caused only
a transient appearance of depolarizing GABAA receptor
mediated responses in neurons that had already started to
shift to mature and more hyperpolarizing EGABA, similar
to what was previously described for the adult neurons. In
contrast, in male neurons, with still depolarizing GABAergic
hyperpolarizing responses. These changes were attributed to
altered expression and/or activity of KCC2 and NKCC1. The
precocious termination of depolarizing GABAA signaling
would be expected to deprive brain from its neurotrophic
effects that are important for normal development [72, 74].
problems when they grow up (unpublished data). How-
ever, the inability of the immature neurons to persistently
exhibit depolarizing GABAA receptor-mediated responses
after seizures could be a protective feature against the devel-
opment of subsequent epilepsy . Our results indicate
that age-specific factors, including the depolarizing GABA,
of CCCs and EGABA through development is the brain-
derived neurotrophic factor (BDNF) pathway, which is also
activated in certain seizure models. BDNF increases KCC2
in developing neurons but decreases it in mature neurons
[172, 173]. The opposite patterns of KCC2 regulation by
BDNF in certain systems has been proposed to be due to
trkB-mediated activation of different intracellular signaling
cascades that regulate KCC2 expression .
The maturation of GABAAreceptor system occurs asyn-
As a result, since early life seizures change the direction
and strength of GABAAreceptor-mediated inhibition, their
effects will be region and cell type specific, further confusing
the interneuronal communication protocols. They may also
disrupt the basic neural processes of learning and cognitive
processing that depend upon GABA neurotransmission,
such as long-term potentiation (LTP) [174–176], or social
interactions [177–182]. The result will be a state of postictal
confusion or more sustained cognitive or behavioral deficits
. Of interest, bumetanide treatment has shown benefit in
five infants with autism . However the exact mecha-
nisms underlying this therapeutic effect are not yet known.
Human and experimental evidence indicates that similar
to adults, aberrant preservation of depolarizing GABAA
signaling may also be a feature of the medically refractory
epileptogenic focus in early life epilepsies. At present we
do not have any data to discuss the pathological features
of the medically sensitive early life epilepsies. The idea
of pharmacologically enhancing GABA inhibition to stop
seizuresbyusingNKCC1 inhibitors likebumetanideisunder
investigation as a rationally developed, smart intervention to
overcome the barriers posed by the well-established molec-
ular switch of GABAA receptor function . Beneficial
effects have been shown in few animal models [21, 186–
189] and a human case report . However, model-spe-
cific differences, as well as the timing of administration,
can influence its efficacy in suppressing seizures [96, 191].
Moreover, concerns have been raised about potential adverse
developmental effects on innocent bystander normal brain
tissues, as may occur in chronic use in patients with focal
epilepsies . Undoubtedly, more studies need to be done
to determine which seizure types are more likely to respond,
when is the optimal time to administer, for how long,
and how such interventions influence long-term outcomes
in subjects who have already experienced seizures or have
epilepsy. Similarly, by increasing our knowledge about the
specific changes that occur in GABAAreceptor composition
and pharmacology, it may be possible to design more
selective and specific GABAAreceptor agonists for the very
young or epileptic brain that is refractory to the existing
medications. At the anatomical and electrophysiological
level, it might be feasible, one day, to design such specific,
inhibition and stop seizures. The biggest challenge will be
however to predict the functional state of GABAAreceptor-
mediated inhibition at the target areas, so as to implement
such rational therapies. Emerging evidence suggests that
GABA-acting drugs, hormones, and different stressors are
among the factors that can alter GABAAreceptor signaling,
rendering it almost a moving target [11, 30, 31, 192–196].
The need for biomarkers of GABAAfunction is therefore a
The study of GABA in seizure generation and consequences
has become a very fruitful field not only by generating
intriguing results but also by producing challenging new
questions. We have learned a number of mechanisms that
brain, predisposing to seizures and the associated cognitive
and neurodevelopmental deficits. We still need to better
understand and, most importantly, predict which is the nor-
specificity, so as to preserve normal brain function and
ADEFS+: Autosomal dominant epilepsy with
febrile seizures plus
ADJME:Autosomal dominant juvenile
ADNFLE: Autosomal dominant nocturnal frontal
ARX: Aristaless-related X-linked homeobox
BDNF:Brain-derived neurotrophic factor
CAE:Childhood absence epilepsy
GABA:Gamma aminobutyric acid
GAD: Glutamic acid decarboxylase
IGE:Idiopathic generalized epilepsy
IPSC:Inhibitory postsynaptic current
3KA-SE: 3 episodes of kainic acid SE at PN4,5,6
KCC:Potassium chloride cotransporter
LTP: Long-term potentiation
NKCC: Sodium potassium chloride
SCN1A: Sodium channel 1A
SMEI:Severe myoclonic epilepsy of infancy
SE: Status epilepticus
TLE:Temporal lobe epilepsy
UBE3A: Ubiquitin-protein ligase 3A.
The authors are grateful for the funding support of NIH
(NINDS/NICHD Grants 62947; NINDS Grant 20253).
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