[Recurrent ischemic strokes revealing Lyme meningovascularitis]. / Une méningovascularite infectieuse de Lyme révélée par des accidents ischémiques cérébraux successifs.

INTRODUCTION: Infectious vascularitis is an unusual cause of ischemic stroke (IS). We report a case of Lyme meningovascularitis complicated with multiple IS. CASE REPORT: A 64-year-old man, without any cardiovascular risk factor, was admitted for a right hemiparesia with a left thalamic hypodensity on the initial cerebral CT scan. No cause for this presumed IS could be identified. Later, the patient developed cognitive impairment and a bilateral cerebellar syndrome. Multiple infarcts and multiple intracranial stenosis were seen on cerebral MRI with magnetic resonance angiography (MRA). Cerebrospinal fluid tests showed meningitis and positive Lyme serology with an intrathecal specific anti-Borrelia antibody index. Antibiotic treatment was followed by good biological and partial clinicoradiological outcome. CONCLUSION: The diagnosis of Lyme neuroborreliosis should be entertained as a possible cause of IS in highly endemic zones.

Modifications of local cerebral glucose utilization in thalamic structures following injection of a dopaminergic agonist in the nucleus accumbens--involvement in antiepileptic effects?

Dopaminergic transmission in the nucleus accumbens (NAcc) is implicated in different aspects of reward and motivational mechanisms. More recently, it has been suggested that this nucleus could also be involved in the modulation of generalized epileptic seizures. In particular, microinjection of dopaminergic agonists in the NAcc suppresses the occurrence of epileptic seizures in a model of absence seizures, the GAERS (generalized absence epileptic rats from Strasbourg). The aim of this study was to identify the structures involved in this effect. Local cerebral metabolic rates for glucose utilization (LCMRglc) were measured in different parts of the basal ganglia and output structures after apomorphine injection in the NAcc in GAERS and in the inbred non-epileptic rats (NE), concomitantly with seizure suppression. Apomorphine injection in the NAcc induced a significant increase of glucose intake in the anteromedial, mediodorsal and ventrolateral nuclei of the thalamus in NE rats, while no significant changes were observed in the basal ganglia structures (globus pallidus, subthalamic nucleus, substantia nigra). Furthermore, microinjections of muscimol (100 and 200 pmol/side) in the mediodorsal nucleus of the thalamus in GAERS rats suppressed seizures. These results suggest that the mediodorsal nucleus of the thalamus could be involved in absence seizures modulation. Along with data from the literature, our data suggest that this nucleus could participate in the control of the basal ganglia over generalized epileptic seizures.

Suppression of absence seizures by electrical and pharmacological activation of the caudal superior colliculus in a genetic model of absence epilepsy in the rat.

Activation of the superior colliculus has been shown to reproduce the antiepileptic effect of the inhibition of the substantia nigra reticulata. A circuit involving neurons of the caudal deep layers of the superior colliculus has been suggested to control brain stem convulsive seizures. The present study was designed to examine whether a similar circuit is also involved in the control of absence seizures. For this, activation of either the rostral or caudal parts of the deep and intermediate layers of the superior colliculus was applied in a genetic model of absence seizures in the rat (GAERS). Single-shock (5 s) electrical stimulation of the rostral and caudal superior colliculus interrupted ongoing spike-and-wave discharges at an intensity (antiepileptic threshold) significantly lower than the intensity inducing behavioral effects. At this intensity, no interruption of licking behavior was observed in water-deprived rats. Repeated stimulations (5 s on/5 s off) at the antiepileptic threshold reduced absence seizures only during the first 10 min. Bilateral microinjection of a GABA antagonist (picrotoxin, 33 pmol/side) significantly suppressed spike-and-wave discharges when applied in the caudal aspect of the superior colliculus. This antiepileptic effect appears dissociated from an anxiogenic effect, as tested in an elevated plus maze test. Finally, bilateral injection of picrotoxin (33 pmol/side) appeared more effective in the superficial and intermediate layers of the caudal superior colliculus, whereas such injections had only weak effects on absence seizures when applied in the deep layers. These results suggest that a specific population of neurons located in the intermediate and superficial layers of the caudal superior colliculus is involved in the inhibitory control of absence seizures. It may constitute an important relay for the control of absence seizures by the basal ganglia via the substantia nigra reticulata.

Medium-voltage 5-9-Hz oscillations give rise to spike-and-wave discharges in a genetic model of absence epilepsy: in vivo dual extracellular recording of thalamic relay and reticular neurons.

In humans with absence epilepsy, spike-and-wave discharges develop in the thalamocortical system during quiet immobile wakefulness or drowsiness. The present study examined the initial stage of the spontaneous development of spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg. Bilateral electrocorticograms were recorded in epileptic and non-epileptic rats under freely moving and undrugged conditions and under neuroleptanalgesia. Short-lasting episodes of medium-voltage 5-9-Hz (mean=6-Hz) oscillations usually emerged spontaneously from a desynchronized electrocorticogram and in bilateral synchrony in both rat strains. These oscillations were distinguishable from sleep spindles regarding their internal frequency, duration, morphology, and moment of occurrence. Spontaneous spike-and-wave discharges developed from such synchronized medium-voltage oscillations, the spike-and-wave complex occurring at the same frequency as the 5-9-Hz wave. Because the thalamus is thought to play a significant role in the generation of spike-and-wave discharges, dual extracellular recording and juxtacellular labelling of relay and reticular neurons were conducted to study the thalamic cellular mechanisms associated with the generation of spike-and-wave discharges. During medium-voltage 5-9-Hz oscillations, discharges of relay and reticular cells had identical patterns in epileptic and non-epileptic rats, consisting of occasional single action potentials and/or bursts (interburst frequency of up to 6-8 Hz) in relay cells, and of rhythmic bursts (up to 12-15 Hz) in reticular neurons, these discharging in the burst mode almost always before relay neurons. The discharge frequency of reticular bursts decelerated to 6 Hz by the beginning of the spike-and-wave discharges. During these, relay and reticular neurons usually fired in synchrony a single action potential or a high-frequency burst of two or three action potentials and a high-frequency burst, respectively, about 12 ms before the spike component of the spike-and-wave complexes. The frequency of these corresponded to the maximal frequency of the thalamocortical burst discharges associated with 5-9-Hz oscillations. The patterns of relay and reticular phasic cellular firings associated with spike-and-wave discharges had temporal characteristics similar to those associated with medium-voltage 5-9-Hz oscillations, suggesting that these normal and epileptic oscillations are underlain by similar thalamic cellular mechanisms. In conclusion, medium-voltage 5-9-Hz oscillations in the thalamocortical loop give rise to spike-and-wave discharges. Such oscillations are not themselves sufficient to initiate spike-and-wave discharges, meaning that genetic factors render thalamocortical networks prone to generate epileptic electrical activity, possibly by decreasing the excitability threshold in reticular cells. While these GABAergic neurons play a key role in the synchronization of glutamatergic relay neurons during seizures, relay cells may participate significantly in the regulation of the recurrence of the spike-and-wave complex. Furthermore, it is very likely that synchronization of relay and reticular cellular discharges during absence seizures is generated in part by corticothalamic inputs.

Inhibition of the substantia nigra suppresses absences and clonic seizures in audiogenic rats, but not tonic seizures: evidence for seizure specificity of the nigral control.

GABAergic inhibition of the substantia nigra pars reticulata has been shown to suppress seizures in most models of epilepsy involving forebrain networks, such as absences or clonic seizures. No such antiepileptic effects were observed, however, in genetically audiogenic rats exhibiting tonic seizures generated in the brainstem. This suggests a constitutive dysfunction of the nigral GABAergic neurotransmission in this strain of rat or a selective action of the nigral control on specific networks. In the present study, we first confirmed that bilateral injection of muscimol (700 pmol/side) in the substantia nigra had no effect in Wistar rats with audiogenic seizures (Wistar AS). [3H]Muscimol autoradiography suggested a 40% reduced density of GABA(A) receptors in the substantia nigra of Wistar AS, whereas no change was observed in the cortex and the superior colliculus (superficial and intermediate layers), as compared to control animals. In Wistar AS where 40 repetitions of audiogenic stimulations progressively induced generalised convulsive seizures with both tonic and clonic components, bilateral injection of muscimol (350 pmol/side) in the substantia nigra suppressed the clonic component but had no effect on tonic seizures. In hybrid rats issued from cross-breeding between Wistar AS and rats with spontaneous absence seizures, bilateral injection of muscimol (18 pmol/side) in the substantia nigra abolished cortical spike-and-wave discharges, but had no effect on tonic audiogenic seizures at doses up to 700 pmol/side. These results show that despite a decreased number of GABA(A) receptors in the substantia nigra, inhibition of this structure in Wistar AS still leads to inhibition of seizures involving forebrain structures. These results confirm that GABAergic inhibition of the substantia nigra has antiepileptic effects through the control of forebrain circuits. They suggest that this control mechanism has no inhibitory effect on circuits underlying audiogenic tonic seizures.

Controlling attentional priority by preventing changes in oculomotor programs: a job for the premotor cortex?

Abruptly presented items capture attention automatically so they constitute the first items to be examined [Yantis and Jonides, Journal of Experimental Psychology: Human Perception and Performance, 1984;10:601; Jonids and Yantis, Perception and Psychophysics, 1988;43:346; Theeuwes, Perception and Psychophysics, 1992;51:599; Theeuwes, Journal of Experimental Psychology: Human Perception and Performance, 1994;20:799]. This attentional priority can be controlled in a top-down manner by directing attention towards the locus of interest [Yantis and Johnson, Journal of Experimental Psychology: Human Perception and Performance, 1990;16:812; Theeuwes. Perception and Psychophysics, 1991;49:83; Miller, Perception and Psychophysics, 1989;45:567; Folk et al., Journal of Experimental Psychology: Human Perception and Performance, 1992; 18:1030]. The premotor theory of attention [Rizzolatti et al., Neuropsychologia 1987;25:31; Rizzolatti et al., Attention and Performance XV, 1994, p. 231] assumes that the mechanism responsible for the attentional shifts is strictly linked to that responsible for eye movements, and several studies [Corbetta et al., Society of Neuroscience Abstracts 1997;23:122.12; Nobre et al., Brain 1997;120:515; Theeuwes et al., Journal of Experimental Psychology: Human Perception and Performance, 1999;25:1595] suggested that the premotor cortex plays a role in the control of attention. However, the nature of this involvement is still unclear. We have been asking a patient (RJ) with a damage of the right premotor cortex to decide whether a target had a discontinuity on its right or left side. The absolute location of the target was pre-cued. In Section 2, an interference was observed when a sudden onset occurred in the visual space, suggesting that RJ was not able to control attentional capture. The possibility to attribute this interference to an insufficient focalization of attention or a grouping effect were discarded by Sections 3 and 4, respectively. Section 5 revealed that this interference followed exclusively the onset occurring in the hemifield opposite the one containing the target (meridian effect [Rizzolatti et al., Neuropsychologia 1987;25:31]). The results suggest that the control of attentional capture may be achieved by keeping constant the parameters of the appropriate oculomotor program.

Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat.

The lithium-pilocarpine (Li-Pilo) model of epilepsy reproduces most of the features of human temporal lobe epilepsy. After having studied the metabolic changes occurring during the silent phase, in the present study, we explored the relationship between interictal metabolic changes and neuronal loss during the chronic phase following status epilepticus (SE) induced by Li-Pilo in 10-day-old (P10), 21-day-old (P21), and adult rats. Rats were observed and their EEG was recorded to detect the occurrence of spontaneous recurrent seizures (SRS). Local cerebral glucose utilization was measured during the interictal period of the chronic phase, between 2 and 7 months after SE, by the [(14)C]2-deoxyglucose method in rats subjected to SE at P10, P21, or as adults. Neuronal damage was assessed by cell counting on adjacent cresyl violet stained sections. When SE was induced at P10, rats did not become epileptic, did not develop lesions and cerebral glucose utilization was in the normal range 7 months later. When SE was induced in adult rats, they all became epileptic after a mean duration of 25 days and developed lesions in the forebrain limbic areas, which were hypometabolic during the interictal period of the chronic phase, 2 months after SE. When SE was induced in P21 rats, 24% developed SRS, and in 43% seizures could be triggered (TS) by handling, after a mean delay of 74 days in both cases. The remaining 33% did not become epileptic (NS). The three groups of P21 rats developed quite comparable lesions mainly in the hilus of the dentate gyrus, lateral thalamus, and entorhinal cortex; at 6 months after SE, the forebrain was hypometabolic in NS and TS rats while it was normo- to slightly hypermetabolic in SRS rats. These data show that interictal metabolic changes are age-dependent. Moreover, there is no obvious correlation, in this model, between interictal hypometabolism and neuronal loss, as reported previously in human temporal lobe epilepsy.

Pallido-Luysio-Nigral atrophy revealed by rapidly progressive hemidystonia: a clinical, radiologic, functional, and neuropathologic study.

Pallido-luysio-nigral atrophy (PLNA) is a rare neurodegenerative disease in which the clinical and radiologic correlates have not yet been clearly established. A 62-year-old man insidiously developed dystonic postures, choreoathetoid movements, slowness, and stiffness, which initially affected the right hand and foot and progressively spread to the entire right side. T2-weighted magnetic resonance imaging showed increased signal intensity in both left and right medial pallida and in the left substantia nigra. Tests using HMPAO-SPECT and FDG-PET demonstrated left cortical hyperperfusion and hypermetabolism, whereas the left lenticular nucleus was slightly hypometabolic. At age 65, abnormal movements and postures involved all four limbs and the axis causing major gait disturbances, and facial and bulbar muscles atrophied resulting in dysarthria, dysphagia, and impaired breathing. Diffuse amyotrophy and fasciculations also appeared. Death occurred at age 66, 4 years after onset. At autopsy, severe bilateral neuronal loss and gliosis restricted to the pallidum, the subthalamic nucleus, the substantia nigra, and the hypoglossal nucleus were noted, accounting for the diagnosis of PLNA with lower motor neuron involvement. Progressive hemidystonia with adult onset represents an unusual clinical presentation for this disorder. Moreover, this observation indicates that a diagnosis of PLNA should be considered for specific magnetic resonance imaging, SPECT, and/or PET data, and suggests that in PLNA, pallidal dysfunction might play a key role in the dystonic presentation.

Future prospects of brain stimulation.

Chronic high frequency (130 Hz) stimulation (HFS) of the thalamic target Vim has replaced thalamotomy as a treatment of tremor of various origins and was extended to two other targets (Subthalamic nucleus (STN) and the medial pallidus (GPi)), since 1993 based on recent experimental data in rats and monkeys. STN appears to be a target of major interest, able to control the three cardinal symptoms and to allow the decrease or suppression of levodopa treatment, which then suppresses also levodopa induced dyskinesias. The mechanisms of action of HFS are not fully understood, but are definitely related to high frequency and are probably different depending on the target. Inhibition of cellular activity or of network functions could be induced, by jamming of a retroactive loop for tremor, or by shutdown of neurotransmitter release in STN. All cardinal symptoms are alleviated from tremor to akinesia and rigidity. The effects remain stable over more than five years chronic HFS of STN, as the method of choice when a surgical procedure is indicated for the treatment of Parkinson's disease and even more when a bilateral procedure is necessary. Recent data show that STN stimulation could be useful in the treatment of dystonia as well as some forms of epilepsies. It is therefore possible that DAS in STN as well as in other targets could become a potent therapeutic tool in the future for neurological disorders. The future of brain stimulation will depend on new technologies (new circuits, electrodes, web based programmers), waveforms (alternatives to square waves, random distribution), targets (hypothalamic nuclei, locus coeruleus) and indications (dystonia, epilepsy, eating disorders.

Selective susceptibility to inhibitors of GABA synthesis and antagonists of GABA(A) receptor in rats with genetic absence epilepsy.

Thalamocortical spike-and-wave discharges characterize the nonconvulsive absence seizures that occur spontaneously in genetic absence epilepsy rats from Strasbourg (GAERS), a selected strain of Wistar rats. GABA is crucial in the generation of absence seizures. The susceptibility to convulsions induced by threshold doses of various GABA receptor antagonists and inhibitors of GABA synthesis, kainic acid and strychnine, was compared in GAERS and in nonepileptic rats from a selected control strain (NE). The brain structures involved in the drug-elicited convulsive seizures were mapped by c-Fos immunohistochemistry. Injection of various antagonists of the GABA(A) receptor, bicuculline and picrotoxin, and inverse agonists of the benzodiazepine site (FG 7142 and DMCM) induced myoclonic spike-and-wave discharges followed by clonic or tonic-clonic seizures with high paroxysmal activity on the cortical EEG. The incidence of the convulsions was dose-dependent and was higher in GAERS than in NE rats. Mapping of c-Fos expression showed that the frontoparietal cortex was constantly involved in the convulsive seizures elicited by a threshold convulsant dose, whereas limbic participation was variable. In contrast, GAERS were less susceptible than NE rats to the tonic-clonic convulsions induced by the inhibitors of glutamate decarboxylase, isoniazide and 3-mercaptopropionic acid. The GABA(B) receptor antagonist CGP 56999 and kainic acid induced a similar incidence of seizures in GAERS and NE rats and predominantly activated the hippocampus. No difference in the tonic seizures elicited by strychnine could be evidenced between the strains. These results suggest that an abnormal cortical GABAergic activity may underlie absence seizures in GAERS.

Pertussis toxin decreases absence seizures and GABA(B) receptor binding in thalamus of a genetically prone rat (GAERS).

Postsynaptic GABA(B) receptor-mediated events have previously been shown to be reduced by prior treatment with pertussis toxin in rat brain. In the present study genetic absence epilepsy rats from Strasbourg (GAERS) were given single bilateral injections of pertussis toxin (PTx 0.4 microg), denatured-PTx or vehicle saline into the relay nuclei of the thalamus under anaesthesia. After recovery the spike and wave discharge duration (SWD) was monitored for up to 6 days following which the brains were removed and GABA(B) or GABA(A) receptor autoradiography performed on 10 microm transverse sections. By 6 days the SWD of the rats treated with PTx was suppressed by 96% compared with vehicle-injected rats with a significant (62%) reduction even after 1 day. Denatured toxin had no effect at any time. After 6 days GABA(B), but not GABA(A), receptor binding was significantly reduced by 70-80% in the ventrolateral and ventral posteriolateral thalamic nuclei. No changes in other brain regions were detected and denatured toxin failed to alter GABA(A) or GABA(B) receptor binding in any brain region. These data implicate G-protein mechanisms in the generation of SWD in GAERS and support the role of GABA(B) receptors in their induction within the thalamus.

Cerebral correlates of hemispheric lateralization during a pitch discrimination task: an ERP study in dichotic situation.

OBJECTIVE: Electrophysiological correlates of perceptual asymmetry for dichotic pitch discrimination were investigated in 12 right-handed volunteers, whose dichotic listening performances attested the classical 'right ear advantage' in a verbal discrimination task. METHODS: Event related potentials (ERPs), elicited by dichotic and binaural pairs of tones applied in a classical oddball paradigm including right ear targets, left ear targets and binaural targets (5% occurrence each) were recorded from medial and lateral scalp locations. Latencies and baseline to peak amplitudes were measured for P1, N1, P2, N2 and P3 components. RESULTS: ERPs recorded in response to dichotic (compared with binaural) target pairs, exhibited delayed latencies for N2 and P3, correlated with prolonged RTs, probably linked to greater difficulty in identification of the target. They also displayed enhanced N1 and P2 voltages, which may reflect the simultaneous activation of two different populations of neurons in the auditory cortical areas. We observed specific lateralization effects for pitch discrimination with a left ear advantage on latency of early components. CONCLUSIONS: Together with amplitude asymmetries in the N2 component, the findings bring strong electrophysiological support to Kimura's structural model for dichotic perceptions with a right hemisphere prevalence in a pitch discrimination task.

C-Fos, Jun D and HSP72 immunoreactivity, and neuronal injury following lithium-pilocarpine induced status epilepticus in immature and adult rats.

In order to follow the maturation-related evolution of neuronal damage, cellular activation and stress response subsequent to Li-Pilo seizures in the 10- (P10), 21-day-old (P21) and adult rat, we analyzed the expression of the c-Fos protein as a marker of cellular activation, HSP72 immunoreactivity as the stress response and silver staining for the assessment of neuronal damage in 20 selected brain regions. The early wave of c-Fos measured at 2 h after the onset of seizures was present in most structures of the animals at the three ages studied and particularly strong in the cerebral cortex, hippocampus and amygdala. The late wave of c-Fos measured at 24 h after the onset of seizures and that was shown to correlate to neuronal damage was absent from the P10 rat brain, and present mainly in the cerebral cortex and hippocampus of P21 and adult rats. The expression of the stress response, assessed by the immunoreactivity of HSP72 at 24 h after the seizures was absent from the P10 rat brain and present in the entorhinal cortex, amygdala, hippocampus and thalamus of P21 and adult rats. The expression of Jun D at 24 h after the seizures was discrete and present in most brain regions at all ages. Neuronal injury assessed by silver staining at 6 h after the onset of seizures was very discrete in the brain of the P10 rat and limited to a few neurons in the piriform and entorhinal cortices. In older animals, marked neuronal degeneration occurred in the cerebral cortex, amygdala, hippocampus, lateral septum and thalamus. Thus the immediate cell activation induced by lithium-pilocarpine seizures which is present at all ages translates only into a late wave of c-Fos and the expression of HSP72 in P21 and adult animals in which there will be extensive cell damage.

Local cerebral glucose utilization in adult and immature GAERS.

In the present study, we compared the basal local cerebral metabolic rates for glucose (LCMRglcs) both in Wistar rats with genetic absence epilepsy (GAERS: genetic absence epilepsy rats from Strasbourg) and in control non epileptic (NE) rats selected in our breeding colony. LCMRglc was measured both in immature rats at postnatal day 21 (P21) at which age no spontaneous spike-and-wave discharges can be recorded in GAERS and at the adult age (6 months) when GAERS fully express thalamo-cortical spike-and-wave discharges recorded on the EEG. LCMRglcs were measured in 24 structures by the quantitative [14C]2-deoxyglucose autoradiographic technique. In adults GAERS, LCMRglc underwent a widespread increase recorded in all brain structures except in mediodorsal and ventromedian thalamus, and in the nucleus accumbens. These metabolic increases ranged from 17 to 50% over control levels in adult NE rats. In P21 GAERS, LCMRglc was similar to that of P21 NE rats in 16 areas. It increased over control levels of NE rats in two groups of structures. Metabolic increases were recorded in four limbic structures (entorhinal and piriform cortices, hippocampus and basolateral amygdala) where no spike-and-wave discharges were recorded in adult GAERS. Increases in LCMRglcs were also located in the substantia nigra pars reticulata, superior colliculus and globus pallidus which are structures involved in the control of seizure activity. In conclusion, our data suggest that the consequences of the genetic mutation(s) underlying the cellular and molecular events responsible for the expression of spike-and-wave discharges in adult GAERS is (are) able to increase metabolic activity in both limbic structures and the nigral inhibitory system before the occurrence of spike-and-wave discharges.

Pathophysiological mechanisms of genetic absence epilepsy in the rat.

Generalized non-convulsive absence seizures are characterized by the occurrence of synchronous and bilateral spike and wave discharges (SWDs) on the electroencephalogram, that are concomitant with a behavioral arrest. Many similarities between rodent and human absence seizures support the use of genetic rodent models, in which spontaneous SWDs occur. This review summarizes data obtained on the neurophysiological and neurochemical mechanisms of absence seizures with special emphasis on the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). EEG recordings from various brain regions and lesion experiments showed that the cortex, the reticular nucleus and the relay nuclei of the thalamus play a predominant role in the development of SWDs. Neither the cortex, nor the thalamus alone can sustain SWDs, indicating that both structures are intimely involved in the genesis of SWDs. Pharmacological data confirmed that both inhibitory and excitatory neurotransmissions are involved in the genesis and control of absence seizures. Whether the generation of SWDs is the result of an excessive cortical excitability, due to an unbalance between inhibition and excitation, or excessive thalamic oscillations, due to abnormal intrinsic neuronal properties under the control of inhibitory GABAergic mechanisms, remains controversial. The thalamo-cortical activity is regulated by several monoaminergic and cholinergic projections. An alteration of the activity of these different ascending inputs may induce a temporary inadequation of the functional state between the cortex and the thalamus and thus promote SWDs. The experimental data are discussed in view of these possible pathophysiological mechanisms.

Intracellular recordings in thalamic neurones during spontaneous spike and wave discharges in rats with absence epilepsy.

1. In vivo extracellular and intracellular recordings were performed from thalamocortical (TC) neurones in a genetic model of absence epilepsy (genetic absence epilepsy rats from Strasbourg) during spontaneous spike and wave discharges (SWDs). 2. Extracellularly recorded single units (n = 14) fired either a single action potential or a high frequency burst of up to three action potentials, concomitantly with the spike component of the spike-wave complex. 3. Three main events characterized the intracellular activity of twenty-six out of twenty-eight TC neurones during SWDs: a small amplitude tonic hyperpolarization that was present throughout the SWD, rhythmic sequences of EPSP/IPSPs occurring concomitantly with the spike-wave complexes, and a small tonic depolarization at the end of the SWD. The rhythmic IPSPs, but not the tonic hyperpolarization, were mediated by activation of GABAA receptors since they reversed in polarity at -68 mV and appeared as depolarizing events when recording with KCl-filled electrodes. 4. The intracellular activity of the remaining two TC neurones consisted of rhythmic low threshold Ca2+ potentials, with a few EPSP/IPSP sequences present at the start of the SWD. 5. These results obtained in a well-established genetic model of absence epilepsy do not support the hypothesis that the intracellular activity of TC neurones during SWDs involves rhythmic sequences of GABAB IPSPs and low threshold Ca2+ potentials.

Forebrain metabolic activation induced by the repetition of audiogenic seizures in Wistar rats.

In Wistar rats susceptible to audiogenic seizures (Wistar AS) inbred in our laboratory, the exposure to an intense sound induces an epileptic seizure characterized by a running episode followed by a tonic phase showing the major involvement of brainstem structures. After 10-20 sound-induced seizures, development of facial and forelimb clonus and/or tonic-clonic seizures characterize the generalization from brainstem to the forebrain as a result of seizure repetition. In order to specify the anatomical substrates of repeated audiogenic seizures in Wistar AS, we used the 2-deoxyglucose (2DG) technique over a 5 min period to map the midbrain and forebrain structures activated by audiogenic seizures before and after seizure repetition. In naive Wistar AS, six of the 22 structures showed a significant 20-56% increase in relative optical densities compared to non-epileptic controls; these were central and medial amygdala nuclei, perirhinal cortex, medial septum, subthalamic and caudate nuclei. In kindled Wistar AS, 12 additional structures showed a significant 16-121% increase in 2DG labeling. These structures were the substantia nigra, all layers of the hippocampus, the basolateral amygdala, three thalamic nuclei, the frontal motor and prefrontal cortices. In conclusion, the metabolic activation of midbrain and forebrain areas in kindled versus naive Wistar AS rats reflects the changes in the nature of the seizures and the involvement of these structures in the spread of seizure activity from the brainstem to the forebrain during seizure repetition.

The amygdala is critical for seizure propagation from brainstem to forebrain.

Audiogenic seizures, a model of brainstem epilepsy, are characterized by a tonic phase (sustained muscular contraction fixing the limbs in a flexed or extended position) associated with a short cortical electroencephalogram flattening. When sound-susceptible rats are exposed to repeated acoustic stimulations, kindled audiogenic seizures, characterized by a clonic phase (facial and forelimb repetitive jerks) associated with cortical spike-waves, progressively appear, suggesting that repetition of brainstem seizures causes a propagation of the epileptic discharge toward the forebrain. In order to determine the structures through which this propagation occurs, four kinds of experiments were performed in non-epileptic rats and in sound-susceptible rats exposed to single or repeated sound stimulations. The following results were obtained: (I) Electrical amygdalar kindling was similar in non-epileptic and naive-susceptible rats, but was facilitated in sound-susceptible rats submitted to 40 acoustic stimulations and presenting kindled audiogenic seizures. (2) Audiogenic seizures induced an increase in [(14)C]2-deoxyglucose concentration in the amygdala after a single seizure, and in the amygdala, hippocampus and perirhinal and piriform cortices after a kindled audiogenic seizure. (3) A single audiogenic seizure induced the expression of c-Fos protein mainly in the auditory nuclei. A few cells were stained in the amygdala. After 5-10 audiogenic seizures, a clear staining appeared in the amygdala, and perirhinal and piriform cortices. The hippocampus expressed c-Fos later, after 40 audiogenic seizures. (4) Injection of lidocaine into the amygdala did not modify single audiogenic seizures, but suppressed myoclonias and cortical spike-waves of kindled audiogenic seizures. Similar deactivation of the hippocampus failed to modify kindled audiogenic seizures. Taken together, these data indicate a critical role for the amygdala in the spread of audiogenic seizures from brainstem to forebrain.

Regional differences of the inhibition of GABAB ligand binding by the GTP analogue Gpp(NH)p.

In order to determine whether the interactions between GABAB receptors and G-proteins differ in several brain areas, we have used the reduction in high-affinity GABAB binding by the GTP analogue Gpp(NH)p as an internal assay marker for G-protein linkage to GABAB receptors. The results indicate that Gpp(NH)p inhibits the binding of the GABAB receptor agonist [3H]CGP 27492 (80 to 95%) in a biphasic manner between 0.1 nM and 1 mM. The IC50 for high-affinity sites is significantly higher in cerebellum (70 nM, 53% of binding sites) than in cortex, hippocampus, corpus striatum and thalamus (15-30 nM, 63-73% of binding sites). The IC50S of the low-affinity sites in hippocampus and cortex (170 microM and 210 microM, respectively) were significantly higher than the IC50S in cerebellum, thalamus and corpus striatum (18-39 microM). All these binding sites are sensitive to pertussis toxin (PTX; 7-15 micrograms/mg protein), implicating that they are linked either to Gi or to Gzero proteins. The two binding sites observed (high affinity, nM and low affinity, microM for Gpp(NH)p) and the regional dependence in affinity of these sites may originate either from different GABAB receptor subtypes, different G-proteins or different coupling mechanisms between G-proteins and GABAB receptors. Whereas the PTX site of G-protein linked to GABAB receptors changes with age [24], the GTP binding site does not differ between peripubertal rats (5-6 weeks) and adults rats (10-12 weeks).