The GABA-Withdrawal Syndrome: A Model of Local Status Epilepticus
International Journal of
The GABA-Withdrawal Syndrome: A Model of Local Status Epilepticus
Carmen Silva-Barrat
Jean Champagnat
Christian Menini
SUMMARY
-
For several years, our group in Gif-sur-Yvette
(France) worked on a model of reflex epilepsy,
the photosensitive epilepsy of Papio papio
baboons
(Killam et al. 1967)
. When these
predisposed baboons are submitted to intermittent
light stimulation, generalized paroxysmal
manifestations appear in the frontal motor cortex
(Morrell et al., 1969)
. We had clearly demonstrated
that generalized paroxysmal manifestations originate
in the motor cortex
(Silva-Barrat et al. 1988)
,
when Simon Brailowsky came to our laboratory.
Simon proposed to block the epileptic
manifestations of baboons by means of a chronic
infusion of ],-aminobutyric acid (GABA) into the
motor cortex of these animals. We performed 4- to
7-day infusions by means of osmotic minipumps
and observed the disappearance of epileptic
manifestations. After cessation of the GABA
infusion, however, a rebound of brain excitability
was observed, as evidenced by the presence of
epileptogenic discharges localized in the infused
area (Bmilowsky et al., 1987; 1989). The phenomenon
appearing after the interruption of the chronic
GABA infusion was named the
"GABAwithdrawal syndrome" (GWS). Initially, we
demonstrated that GWS is not the consequence of
the genetic epileptic predispositon of baboons,
and we tested the effects of chronic intracortical
GABA infusions in non-photosensitive animals.
Indeed, we reproduced GWS not only in
nonepileptic baboons but also in normal rats. After
returning to Mexico, Simon and his group
reproduced GWS in hippocampal slices of rats
(Garciaugalde et al., 1992). Finally, this phenomenon
could be considered a new model of focal epilepsy
(Brailowsky et al., 1988)
. Thanks to this discovery, a
new series of epileptic studies has been initiated that
we want to present briefly as our tribute to Simon.
GWS AS A MODEL OF LOCAL STATUS
EPILEPTICUS IN THE RAT: IN VIVO AND
IN VITRO STUDIES.
Both EEG and clinical studies
(Brailowsky et
al., 1988)
have established that GWS is a status
epilepticus resembling the epilepsia partialis
continua, a partial status epilepticus that was
described in human patients by Kojewnikow
(1895). GABA is infused into the motor cortex of
rats for 5 days. Upon cessation of the infusion,
an epileptogenic focus appears, characterized by
continuous EEG discharges at high frequency,
localized in the infused area and associated with
myoclonic twitches ofthe contralateral corresponding
body territory. The epileptic manifestations appear
20 min after the infusion interruption, persist for
48 h on average, and never generalize into
tonicclonic seizures. GWS is an interesting model
resulting from a local manipulation that is
associated with a focal epilepsy. GWS is
different from other epilepsy models that are
provoked by topical application of toxic or
irritant drugs or even convulsant drugs (such as
penicillin, kainate or pilocarpine) provoking
diffuse abnormalities.
Using conventional intracellular recording
and stimulation techniques, we studied neuronal
activity in the epileptogenic focus in neocortical
slices obtained from rats presenting GWS
(SilvaBarrat et al., 1989). The presence of a great
number of burst-generating neurons in an area
close to the GABA-infused site has enabled the
analysis of epileptic-like pattern generation by
comparing bursting and nonbursting cells.
Bursting neurons present paroxysmal depolarizing
shifts (PDSs) and bursts of action potentials
(APs) after synaptic activation by white matter
stimulation (WM) and/or intrinsic bursts of APs
after intracellular injection with a depolarizing
current. Nonbursting neurons present neither
synaptic nor intrinsic bursting properties. In this
paper, we will first describe the cellular types
recorded in the GWS epileptic focus, and we will
show that the bursting cells are desensitized to
GABA. We will also present some ionic mechanisms
that are involved in the genesis of the epileptic
activity, and finally discuss some
neuromodulatory mechanisms involved in this activity.
PHYSIOLOGICAL AND MORPHOLOGICAL
IDENTIFICATION OF NEURONS SHOWING
BURSTING ACTIVITY
Histological observation of slices showed that
the recorded cells are impaled at the periphery of
the necrotic zone (0.7 to 1.2 mm) because of
cannula penetration and GABA infusion. The
soma of biocytine-labeled neurons are localized
in layer V (Fig. 1A). Cells presenting synaptic
and/or intrinsic bursts have a pyramidal-shaped
soma with a basal dendritic arborization, an
apical dendrite, and an axon from the basal region
of the soma (Fig. 1B)
(Silva-Barrat et al., 1994)
.
Synaptic bursts are evoked by suprathreshold
white matter stimulation. The bursts consist of
38 APs riding on the large depolarizing wave or
PDS, EPSPs are obtained by decreasing the
stimulus intensity to values subthreshold for AP
elicitation (Fig. 1C). Intrinsic bur (...truncated)