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Inhibition and Epilepsy
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Inhibition and Epilepsy
Citation:
Avoli, M (2004) History of Neuroscience: Inhibition and Epilepsy, IBRO History of Neuroscience
[http://www.ibro.info/Pub/Pub_Main_Display.asp?LC_Docs_ID=3535]
Accessed: date
Massimo Avoli
Recurrence of paroxysmal neurological and/or behavioral manifestations, commonly termed
seizures, is the hallmark of epilepsy. Epileptic seizures are generally considered hyperexcitable
phenomena resulting from a chronic imbalance between excitatory and inhibitory events. Hence,
since GABA is the major inhibitory transmitter in the CNS, impairment of GABA function should lead
to seizures, while enhancing its efficacy may exert an anticonvulsant action. Reviews of the role
played by GABA in seizure generation and epileptogenesis have appeared in the last few years (3,
23).
Today, it is well established that postsynaptic activation of GABAA receptors mediates fast
inhibition caused by a Cl- conductance, while GABAB receptor activation leads to a relatively slow
form of inhibition due to a G-protein-linked, increase in K+ conductance (Figure 1A). In both cases
GABA acts by increasing the membrane conductance for ions that have an equilibrium potential
near or more negative than the resting membrane potential. In this way neurons hyperpolarize,
thus preventing action potential firing. GABAB (and perhaps GABAA ) receptors are also found on
the nerve endings of cortical neurons where they inhibit transmitter release by reducing Ca2+
entry. When they are localized at excitatory terminals, activation of GABAB receptors inhibits
glutamate release and thus the overall effect is a decrease in excitation (Figure 1B). However,
when they are situated at inhibitory terminals (these receptors are also known as autoreceptors)
their activation causes a decreased release of GABA (Figure 1C), which may in turn result in
neuronal network excitation.
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Figure 1: A: Cortical GABA-mediated postsynaptic potentials; monosynaptic inhibitory re¬sponse
recorded with a K-acetate-filled, intracellular electrode in a human cortical neuron in the presence
of ionotropic excitatory amino acid receptor antagonists (Control). The arrows point at the fast
and slow hyperpolarizations mediated by the activation of type A and type B GABA receptors,
respectively. This conclusion is derived from the pharmacological analysis performed with the
GABAA receptor antagonist bicuculline methiodide (BMI) and the GABAB receptor antagonist P3aminopropyl, P-diethoxymethyl phosphoric acid (CGP 35348). B & C: GABA-mediated presynaptic
inhibition; in B, activation of the GABAB receptors following application of baclofen leads to
blockade of both hyperpolarizing and depolarizing spontaneous postsynaptic potentials recorded
with a K-acetate/QX314-filled electrode from a CA3 pyramidal neuron treated with 4aminopyridine. This effect is reversed by applying the GABAB receptor antagonist CGP-35348. In
C, paired-pulse depression of the monosynaptic inhibitory responses recorded with a KCl/QX314filled electrode from a bursting neuron in the rat subicular cortex under control (i.e. during
application of ionotropic amino acid receptor antagonist) and after bath application of the GABAB
receptor antagonist CGP-35348. Paired pulse depression is not seen under the latter conditions
thus indicating the participation of GABAB receptors in the reduction of the amplitude of the
response induced by the second stimulus. From Avoli 2000.
The oldest demonstration of a relation between GABA and seizures rests on the occurrence of
convulsions in infants fed with a formula accidentally made deficient in pyridoxine during
processing (17). Pyridoxine, known also as vitamin B6, is the coenzyme for the formation of GABA
from glutamic acid by means of the enzyme glutamic acid decarboxylase (GAD). Several studies
have later confirmed that substances capable of interfering with GABA synthesis, release or
postsynaptic effects cause convulsions in vivo or epileptiform synchronization in vitro. Moreover,
weakening and/or blockade of GABA-mediated inhibition have been reported to occur shortly
before the onset of seizure activity in several animal models of epileptiform discharge both in vivo
and in vitro (3).
The relevance of these data within the context of chronic epileptic disorders remains debatable. In
fact most of this evidence has been obtained in normal brains subjected to 'acute' manipulations.
Some studies have shown that particular types of cortical (neocortex and hippocampus)
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GABAergic cells are not damaged in animal models of mesial temporal lobe epilepsy and in epileptic
patients (14). However, other authors have observed a loss of GABAergic neurons and axon
terminals in human sclerotic epileptic hippocampus, being basket cells and chandelier cells two of
the interneuronal types affected (1). It has been also reported that decreased inhibitory control
within the epileptic limbic system results from the functional disconnection of interneurons from
excitatory inputs (11, 27, 29). Functional changes in inhibitory mechanisms in patients with mesial
temporal lobe epilepsy may also relate to deficits in GABA transporter function (30) or alterations
in GABAA receptor subunit composition (13, 18, 24). Indeed, GABAA receptor function in the
dentate gyrus of epileptic animals is altered by Zn2+ (6, 7). This represents an interesting
mechanism as the reorganized mossy fibers in the dentate gyrus contain this metal.
Emerging evidence indicates that GABA may promote epileptiform synchronization. For instance,
GABA receptor-mediated inhibition can facilitate the thalamocortical processes leading to the
occurrence of generalized spike and wave discharges that occur during absence seizures in
primary generalized epilepsy. The synchronous activity generated by thalamocortical relay cells is
regulated by the inhibitory inputs that originate from neurons of the thalamic nucleus reticularis (9,
15). These inputs elicit both fast GABAA and slow GABAB receptor-mediated hyperpolarizing IPSPs
that cause rebound action potential bursts in thalamocortical relay neurons, thanks to deinactivation of a T-type Ca2+ current. The thalamocortical volleys in turn excite cortical cells that
re-excite nucleus reticularis neurons via corticothalamic connections. Hence, hypersynchrony
within the thalamocorticothalamic loop can be insured through GABA receptor-mediated
mechanisms that re-configure the thalamocortical network operation into patterns of activity
characteristic of spike and wave discharge. Data obtained from slices obtained from beta3
knockout mice has confirmed that the excitability of nucleus reticularis neurons modulates
thalamocortical oscillatory synchrony (16). Moreover, intraperitoneal injection of GABA mimetics
induces a dose-dependent increase in the duration of the spike and wave discharges in several
genetic models of absence seizures (10, 12, 21). Early studies performed in the model of feline
generalized penicillin epilepsy have also indicated that GABAA receptor-mediated potentials are still
operant in neocortical cells that participate in spike and wave discharges (5).
GABAA receptor-activated channels can also depolarize cortical neurons. Indeed, GABAA -mediated
depolarizations can be recorded following intense synaptic activation or during application of 4aminopyridine, and they often result from the activation of GABAA receptors located on dendrites
(Figure 2). This might imply that [Cl- ]i in the dendrites of cortical neurons is much higher than in
the soma, where hyperpolarizations are recorded. However, GABAA receptor-mediated
depolarizations also occur because GABAA receptor-activated channels can become permeable to
HCO3-, an anion with equilibrium potential more positive than Cl- (19, 28). GABAA receptormediated depolarizing postsynaptic responses are also contributed by an increase in [K+]o that
may be largely dependent on the HCO3- conductance (4). Moreover, intense synaptic activation of
GABAA receptors in the adult hippocampus leads to Ca2+ neuronal uptake through the activation
of voltage-gated Ca2+ channels by the HCO3--dependent depolarization (2). GABAA receptormediated depolarizations have been recorded in the guinea-pig hippocampus from inhibitory
interneurons of the dentate hilus where they contribute to interneuron synchronization (22).
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Figure 2: GABA-mediated long-lasting depolarizations (asterisks) generated by a hippocampal
neuron during application of low concentrations of the K+ channel blocker 4-aminopyridine
(Control) in response to stratum (s.) radiatum stimulation or spontaneously, but not following
alvear stimuli. Note that the long-lasting depolarizations are preceded by an early (GABAA receptor-mediated) hyperpolarizing potential and followed by a long-lasting (GABAB -receptormediated) hyperpolarization. Local application of bicuculline methiodide (BMI) to the apical
dendrites causes a selective depression of both evoked and spontaneous long-lasting
depolarizations whereas the antidromic recurrent IPSP is still recorded. From Avoli 2000.
Activation of GABAA receptors leading to elevation in [K+]o can paradoxically initiate ictal activity
in the CA3 area of the young rat hippocampus (Figure 3A) and in the adult rat or mouse entorhinal
cortex (Figure 3B).
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Figure 3: GABA-mediated synchronization leads to the onset of epileptiform discharge during
application of 4-aminopyridine. A: Simultaneous field potential (Field) and intracellular (Intra)
recordings performed in the CA3 area of a 22-day-old rat. The onset of the ictal discharge is
illustrated at an expanded time base to show details of the initial GABA-mediated potential and
subsequent ictal discharge. B: Simultaneous field potential (Field) and [K+]o recordings performed
in the adult rat entorhinal cortex show the occurrence of spontaneous negative potentials that
are associated with increases in [K+]o (a). In b, an ictal discharge is initiated by a negative-going
potential. Note that [K+]o increases during this negative potential (arrow) and attains values that
are larger than those associated with the isolated negative-going potentials. From Avoli 2000.
Hence, GABA receptor-mediated synchronization may serve as a powerful implement for the
initiation of epileptiform activity. It is well known that increasing [K+]o induces a positive shift of
GABA-mediated postsynaptic inhibition, depolarizes neurons and disinhibits excitatory postsynaptic
interaction. The facilitatory effects of GABA receptor mechanisms in implementing ictal discharges
is supported by the ability of pharmacological procedures that interfere with GABAergic
transmission (e.g. activation of µ-opioid receptors causing interneuron hyperpolarization and thus
a decreased GABA release) to abolish GABA-mediated synchronous potentials along with the ictallike discharges (Figure 4).
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Figure 4: Pharmacological demonstration of the role played by the synchronus GABA-mediated
potential in the initiation of ictal discharges in juvenile hippocampus (A) and in the adult entorhinal
cortex (B). A: Activation of µ-opioid receptors by DAGO ([D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin),
which abolishes GABA release from interneuron terminals, blocks both GABA-mediated field
potentials and ictal discharges recorded with field potential and [K+]o recordings during application
of 4-aminopyridine in the CA3 subfiled of a hippocampal slice obtained from a young rat
hippocampus. From ref 63. B: Similar effects are seen during DAGO application to a combined
hippocampal-entorhinal cortex slice that was also treated with 4-aminopyridine. In this experiment
field potential recordings were obtained from the entorhinal cortex (EC) and the CA3 subfield. Note
that interictal discharges continue to occur in both experiments. From Avoli 2000.
Synchronous GABAA receptor-mediated depolarizing potentials are also generated spontaneously
by hippocampal neurons early in life (8). It has been proposed that these depolarizing events
represent a key element for controlling several Ca2+-dependent developmental phenomena that
include cell proliferation, migration and targeting (20, 26). The molecular and cellular mechanisms
responsible for the generation of these GABAA -mediated depolarizations in each of these specific
conditions remain unclear. However, recent findings indicate that the ontogenetic changes in
GABAA receptor-mediated responses from depolarizing to hyperpolarizing is coupled to a
developmental expression in neurons of a Cl--extruding K+/Cl- co-transporter, that may also
represent the main promoter of fast hyperpolarizing postsynaptic inhibition in the mature brain
(25).
Over fifty years of research on GABA functions have made possible to identify several actions that
are mediated by this neurotransmitter. Indeed, when expressed in the complexity of the brain
function, the role of GABA receptors goes far beyond the original inhibitory role described in early
studies. As a result we face today scenarios that are at times in antithesis with the simple view
that seizures stem from a decrease in GABA receptor-mediated inhibition. Nonetheless, one must
recognize that epileptiform discharges, whether caused by a mechanism related to GABA function
or not, can be controlled by GABA strategies that include the use of traditional pharmacological
approaches that increase the efficacy of GABA receptor-mediated mechanisms.
Massimo Avoli
Montreal Neurological Institute and Departments of Neurology & Neurosurgery and Physiology
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McGill University
Montreal, Que., H3A 2B4, Canada
Dipartimento di Fisiologia Umana e Farmacologia, Università di Roma "La Sapienza", 00185 Roma,
Italy
IRCCS Neuromed, 86077, Pozzilli (IS) Italy
[email protected]
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