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Department of Clinical Neuroscience, Institute of Psychiatry, London, England
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONIonotropic glutamate receptorsMetabotropic glutamate receptorsGlutamate release and epilepsyREFERENCES |
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KEY WORDS: • epilepsy • glutamate • N-methyl-D-aspartate • kindling • glutamate metabotropic receptors • antiepileptics
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONIonotropic glutamate receptorsMetabotropic glutamate receptorsGlutamate release and epilepsyREFERENCES |
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, Burgess and Noebels 1999
). To
date, no mutations directly involving glutamatergic transmitter
mechanisms have been identified (see Meldrum and Chapman 1999b
). Nevertheless, seizures can be provoked in
epileptic and nonepileptic animals and humans by a wide number of
glutamatergic molecular mechanisms. Despite the varied primary
pathology of epileptic seizures, the mechanisms involved in generating
and spreading epileptic discharges converge on a common cellular
pathology in which the excitatory glutamatergic system plays a key
role. Compelling neurophysiologic, pharmacologic, biochemical and
anatomical evidence has been accumulated over the last several decades
firmly implicating ionotropic
N-methyl-D-aspartate
(NMDA),2
and 
-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid
(AMPA)/kainate and metabotropic glutamate receptor-mediated
mechanisms in epileptic seizures. Excitatory glutamatergic mechanisms
are involved during both acute, transient, evoked seizures and
long-term, adaptive cellular plasticity associated with
epileptogenesis in chronic epilepsy models such as amygdala-kindled
rats or rats with spontaneous, recurring seizures after an early
episode of induced status epilepticus. This brief overview will list
some of the key observations supporting such a link. |
Ionotropic glutamate receptors |
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TOPABSTRACTINTRODUCTIONIonotropic glutamate receptorsMetabotropic glutamate receptorsGlutamate release and epilepsyREFERENCES |
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Glutamate (and aspartate or other excitatory endogenous compounds such as quinolinate or some sulfur-containing amino acids, as well as more potent selective agonists including NMDA, AMPA, kainate, ibotenic acid and domoic acid) can cause convulsions when administered focally or systemically to experimental animals. Glutamate exerts its excitatory action via ligand-gated ion channels (NMDA and non-NMDA receptors) to increase sodium and calcium conductance, and a myriad of reciprocal regulatory interactions exist between the activation of glutamatergic receptors and other transmitter systems, ion transport, gene activation and receptor modification. The flexibility and complexity of these interactions place glutamate-mediated transmission in a pivotal position for modulating the excitatory threshold of pathways involved in seizure generation.
Intracellular recordings in an epileptic focus during "spike discharges" or in a normal cortical neuron during generalized seizure activity reveal a so-called "paroxysmal depolarizing shift" associated with a burst of membrane spikes. This depolarization is analogous to a giant excitatory synaptic potential; its earliest component is due to activation of AMPA receptors and its later component to activation of NMDA receptors.
The anticonvulsant properties of ionotropic glutamate receptor
antagonists have been comprehensively reviewed recently (Chapman 1995
, Meldrum 1995
, Meldrum and Chapman 1999a
, Rogawski 1992
). All classes of NMDA
receptor antagonists (competitive NMDA antagonists, channel site
antagonists, glycine site antagonists, polyamine site antagonists), as
well as competitive and noncompetitive AMPA/kainate antagonists,
display wide-spectrum anticonvulsant properties in acute and
chronic animal epilepsy models, with varying degrees of behavioral side
effects, ranging from minimal for some of the glycine site or
competitive NMDA antagonists, to extensive for some of the high
affinity open-channel NMDA antagonists. To date, limited "add-on
trials" in epileptic patients with some of the NMDA antagonists
[CPPene, dizocilpine (MK-801) and dextromethorphan] have failed to
demonstrate a therapeutic benefit of these antagonists against
refractory complex partial epilepsy.
Although it has been shown that complete elimination of the NR1 subunit
of the NMDA receptor is incompatible with survival in NR1
"knockout" mice (Forrest et al. 1994
), the modest
down-regulation of NMDA receptor subunits produced by antisense
probes against the NMDA receptor NR1 subunit provides complete
protection against sound-induced seizures in audiogenic mice
(Chapman et al. 1996
) or increases the latency to
NMDA-induced seizures in Swiss mice (Zapata et al. 1997
). Conversely, the overexpression (by focal injection of
the appropriate vectors) of the kainate receptor, GluR6, in the
hippocampus, or the AMPA receptor subunit, GluR1, in the deep
prepiriform cortex, facilitates seizures (see Chapman 1998
).
Changes in ionotropic glutamate receptors and glutamate transporters in epilepsy.
The effect of various mutations of glutamatergic receptor subunits on
seizure susceptibility can be studied by genetic manipulation in
transgenic mice. Conversely, the effect of sustained or chronic
seizures on the levels and characteristics of glutamatergic receptors
and their corresponding mRNA expression can be studied in resected
human epileptic tissue, or in genetic and other chronic animal epilepsy
models. Examples of altered glutamate receptors brought about by
genetic manipulation include the lethal global elimination of the NMDA
receptor subunit NR1 mentioned above. Anatomically restricted (to the
hippocampal CA1 region) NR1 knockouts, or combined gene disruption of
NMDA-NR2A and NR2C, cause some impairment of plasticity or motor
coordination, respectively, but no seizures (see Chapman 1998
).
Transgenic mice with an editing-deficient AMPA receptor subunit,
GluR2, display early onset of epilepsy. The GluR2 subunit confers an
almost complete block of calcium conductance in homomeric or
heteromeric AMPA receptors. Both the GluR2 receptor level and the RNA
editing process are reduced significantly, and the corresponding
AMPA-evoked calcium current in pyramidal neurons increased
significantly in accordance with the enhanced seizure susceptibility in
these mice (Brusa et al. 1995
, see Chapman and Meldrum 1999
).
Neuronal (EAAC-1) and glial (GLT-1 and GLAST) glutamate transporters
facilitate glutamate and aspartate reuptake after synaptic release. A
down-regulation of glutamate transporters would be compatible with
enhanced excitatory activity. Transgenic mice with GLT-1 knockout
display spontaneous epileptic activity (Tanaka et al. 1997
), and mice treated chronically with antisense probes to
EAAC-1 (and to a much lesser extent with antisense probes to GLT-1 or
GLAST) show reduced transporter levels and increased epileptic activity
(Rothstein et al. 1996
).
The reported changes in glutamate receptors and transporters subsequent
to sustained or chronic epilepsy are less consistent and frequently
transient in nature; some of these changes reflect patterns of cell
loss. A functional enhancement of NMDA receptors is observed in
amygdala-kindled rats and in resected tissue from humans with
temporal lobe epilepsy (Mody 1998
). The molecular
alterations in the NMDA receptor responsible for this functional
up-regulation are not clearly defined but probably involve altered
phosphorylation.
Changes in the editing of the GluR2 AMPA subunit (which confers block
of calcium conductance as mentioned above) have been reported in
resected hippocampi from some patients with refractory epilepsy
(Grigorenko et al. 1997
). The mRNA levels of
multiple AMPA subunits are also altered in kindled rats and in rats
after sustained seizure activity evoked by kainate or pilocarpine (see
Chapman and Meldrum 1999
).
|
Metabotropic glutamate receptors |
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TOPABSTRACTINTRODUCTIONIonotropic glutamate receptorsMetabotropic glutamate receptorsGlutamate release and epilepsyREFERENCES |
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The classification of metabotropic glutamate receptors into three
functional groups on the bases of their sequence homology, second
messenger effectors and pharmacology is discussed elsewhere in this
volume (Dingledine and Conn 2000
, Meldrum 2000
). In brief, Group I comprises mGluR1 and mGluR5, which are
linked via G proteins to activation of phospholipase C. Group II
(mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, mGluR7, mGluR8) are
both negatively linked to adenylyl cyclase activation.
Until recently, the metabotropic ligands available have not had sufficient bioavailability, potency or selectivity to permit a confident assignment of physiologic and pharmacologic properties to the individual metabotropic receptors. A pattern is gradually emerging, however, concerning the proconvulsant and anticonvulsant activities of agonists and antagonists acting at the different groups of metabotropic receptors; this will be summarized below.
Activation of Group I mGluR enhances neuronal excitability by several
mechanisms (blockade of accommodation to a steady current, potentiation
of the effects of NMDA and AMPA and depolarization); accordingly,
agonists acting on Group I receptors (e.g., 3,5-dihydroxyphenylglycine)
have convulsant activity (Ghauri et al. 1996
,
Tizzano et al. 1995
). Conversely, Group I antagonists,
both those selective for mGluR1 (e.g., AIDA and LY 367385) and for
mGlu5 (e.g. MPEP and SIB 1893) have anticonvulsant activity in several
experimental seizure models (Chapman et al. 1999
and 2000
, Thomsen et al. 1994
).
Activation of Group II and Group III receptors by reasonably selective
agonists appears to have mixed convulsant/anticonvulsant action,
although a prolonged anticonvulsant action seems to predominate
(Tang et al. 1997
, Tizzano et al. 1995
).
The proconvulsant or anticonvulsant action of antagonists acting at
Group II and Group III metabotropic receptors fails to conform to any
consistent, coherent pattern.
Changes in metabotropic glutamate receptors in epilepsy.
Knockout mutations of metabotropic receptors, in particular mGluR1 and
mGluR5, in transgenic mice affect plasticity and long-term
potentiation, but produce no overt seizure disorders (Bordi et al. 1997
, Ferraguti et al. 1997
, Lu et al. 1997
).
Long-lasting functional enhancement of Group I mGluR activity
(Akiyama et al. 1992
) and Group II and Group III
metabotropic receptors (Neugebauer et al. 1997
) has been
reported in amygdala-kindled rats. There is a transient inverse
alteration of Group I receptor levels (increased mGluR1; decreased
mGluR5) in kindled rats (Akbar et al. 1996
).
|
Glutamate release and epilepsy |
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TOPABSTRACTINTRODUCTIONIonotropic glutamate receptorsMetabotropic glutamate receptorsGlutamate release and epilepsyREFERENCES |
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It has been possible to measure extracellular glutamate levels via
microdialysis probes implanted into the hippocampus in association with
the implantment of electroencephalogram (EEG) electrodes in
drug-refractory epileptic patients undergoing depth-electrode
EEG recordings and telemetry evaluation of their seizure focus as
preparation for an eventual surgical resection (Chapman 1997
). During spontaneous seizures in ambulatory patients,
there is a marked, bilateral, transient ictal increase in extracellular
hippocampal glutamate levels, which is largest in the epileptic
hemisphere (During and Spencer 1993
, Wilson et al. 1996
). Similar increases in glutamate release can be
observed associated with evoked seizures during surgery in epileptic
patients (Ronne-Engström et al. 1992
).
Glutamate release during seizures in rodents with chronic epilepsy.
Enhanced in vivo glutamate release is generally not observed during
acute, evoked seizures in experimental animals. However, in chronic
epilepsy models in rodents (amygdala-kindled rats, genetically epilepsy
prone rats, rats with spontaneous, recurrent seizures after
kainate-induced status epilepticus), there appears to be a
consistent marked increase in glutamate release during seizures (see
Chapman 1998
).
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FOOTNOTES |
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2 Abbreviations used: AMPA,
-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid; EAAC, neuronal
glutamate and aspartate transporter; EEG, electroencephalogram; GLAST,
glial glutamate and aspartate transporter; GLT, glial glutamate
transporter; NMDA, N-methyl-D-aspartate.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONIonotropic glutamate receptorsMetabotropic glutamate receptorsGlutamate release and epilepsyREFERENCES |
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