Biomedical subjects
Publications and source records attributed to Y Ben-Ari.
Autoradiographic localization of kainate binding sites has been determined in developing human and rat hippocampi. The results suggest differences. In particular, a transient high density of sites occurs in the supragranular layer of the fascia dentata of the human hippocampus.
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Congenital depression of the neonatal skull has had an incidence of 0.1% (1/10 000) in our newborn population during the past 8 years. These skull depressions have two pathogenetic types: deformation without fracture and fracture accompanied by depression. The cause of skull depression being the pressure exerted by the digits and fist of the newborn on his skull has not been previously reported. The treatment of choice for selected cases is nonsurgical elevation with an obstetric vacuum extractor. A CT scan should be performed prior to this treatment to rule out intracranial complications such as hemorrhage.
[3H]Kainic acid binding sites with a slow dissociation rate in the rat limbic system were investigated in detail. Extensively washed membranes prepared from the hippocampal formation and from the region comprising the amygdala and the piriform cortex yielded non-linear Scatchard plots. Microdissection showed that the high-affinity component (affinity constant around 1 nM) was present in the hippocampal CA3 region (4.2 fmol/mg wet tissue) and the amygdaloid complex (4.6 fmol/mg wet tissue), whereas the remaining part of the hippocampal formation and the piriform lobe contained the low-affinity component (affinity constant 5-20 nM; 11.6 and 11.3 fmol/mg wet tissue, respectively). In the lateral + medial septum we detected only the low-affinity component. Severe limbic seizures, induced by unilateral injection of 0.7 or 0.8 microgram kainic acid in 0.3 microliter of phosphate-buffered saline into the amygdala, reduced kainic acid binding sites in the ipsilateral amygdala and CA3 region. The decline of kainic acid binding sites in the injected amygdala was followed by a similar effect in the contralateral amygdala ("mirror focus") and later by a moderate loss also in the contralateral CA3 region. Kainic acid receptor autoradiography demonstrated that binding sites were lost from the stratum lucidum in hippocampus. Septal lesion had no effect on kainic acid binding sites in the hippocampus. Comparison with previous results on the histopathological changes after this lesion shows that high-affinity kainic acid binding sites are preferentially located on neurons that undergo selective degenerations after severe kainic acid-induced seizures.
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Autoradiographic localization of kainic acid binding sites has been determined in postmortem human hippocampi. The results reveal that these binding sites are present in regions vulnerable to epilepsy, in particular the terminal field of the mossy fibers.
In rats anaesthetized with urethane, push pull cannulae were stereotaxically introduced in the hippocampus (bilaterally) and Zn2+ assayed in the perfusate by atomic absorption spectrophotometry. When the cannula was located in the immediate vicinity of the mossy fiber zone, both spontaneous and K+ evoked release of Zn2+ were observed, this release was associated with a reduction in the histologically demonstrable Zn2+ as assessed by means of the Timm's stain. Neither spontaneous nor evoked release of Zn2+ was observed when the cannula was located in the medial part of CA1, the fimbria or the thalamus. These observations suggest that Zn2+ is released in the mossy fiber zone.
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In rats up to 16 days after birth, parenteral kainic acid (KA) produced tonico-clonic convulsions, metabolic activation limited to the hippocampus, and no brain damage. Starting with the 19th day after birth, KA produced limbic seizures associated with metabolic activation and subsequent damage in the hippocampus, the amygdala, and other limbic structures. Membranes prepared from hippocampi 10 days after birth bound [3H]KA with a high affinity component, which was localized in the mossy fiber region by slice autoradiography. In contrast, on amygdaloid membranes this component appeared only 17-19 days after birth. Our results further stress the crucial role of the amygdala in the KA seizure syndrome.
In rats under urethane anaesthesia gamma-aminobutyric acid agonists and uptake blockers were microiontophoretically applied in the pyramidal layer of CA1 and in the apical dendrites using a twin set of multibarrelled micropipettes. Thus, the somatic and dendritic field potentials elicited by commissural stimulation were recorded simultaneously and the effects of iontophoretic applications at either site studied. Somatic applications of gamma-aminobutyric acid, isoguvacine or muscimol produced an inhibition of the somatic population spike; this showed rapid fade and was followed by an "off" response i.e. an enhancement of the population spike discharge and the occurrence of a second (and occasionally third) spike. The order of potency with regard to the "off" response was muscimol greater than isoguvacine much greater than gamma-aminobutyric acid. In contrast, the inhibition of the population spike produced by 4,5,6,7-tetrahydroisoxazolo(5,4-C) pyridin 3-OL showed little fade and no prominent "off" response. The fade and "off" response were not associated with significant changes in the dendritic field excitatory postsynaptic potential concommittantly recorded and were exclusively restricted to the immediate vicinity of the pyramidal layer. Ejection of gamma-aminobutyric acid and its agonists in the stratum radiatum produced a reduction of the field excitatory postsynaptic potential and the somatic spike, this effect however showed no fade (even during prolonged applications of high doses) and no "off" response. Somatic applications of the uptake blockers nipecotic acid or guvacine consistently produced: an increase in the effectiveness of the inhibition produced by gamma-aminobutyric acid and its analogues: a decrease in the latency to peak of the inhibition and an increase in the time to recovery; a full blockade of the fade and the "off" response. All of these effects were rapid and fully reversible without significant changes in either the field excitatory postsynaptic potential or the (control) somatic spikes. The more specific glial uptake blocker, 4,5,6,7-tetrahydroisoxazolo(4,5-C) pyridin 3-OL occasionally blocked the "off" response, however it was less potent and also tended to reduce the spike amplitude. Dendritic applications of the uptake blockers reduced the excitatory postsynaptic potential and the somatic spike but failed to produce prominent changes in the action of gamma-aminobutyric acid and its analogues.(ABSTRACT TRUNCATED AT 400 WORDS)
Folic acid has been injected unilaterally into the amygdaloid complex of awake chronically implanted rats, or in rats under anaesthesia. Clinical, electrographic, and metabolic changes (estimated by means of the 2-deoxyglucose method) have been studied in relation to subsequently demonstrated neuropathology using Fink-Heimer and Nissl stains. The observations are compared to the corresponding effects of intra-amygdaloid application of kainic acid. Major differences were noted between the folate and the kainate induced seizure/brain damage syndrome. Thus: folate produced essentially stereotypies, alternating with myoclonic unilateral jerks of head and limbs. In contrast, limbic motor seizures which are characteristically produced by kainic acid, were extremely rare. Folate did not produce the preferential and sequential electrographic activation of limbic structures as observed after kainate. 2-Deoxyglucose autoradiography revealed an enhanced metabolic activity in the injected amygdala and in the overlying piriform and entorhinal cortices. The most conspicuous rise in labelling, however, occurred in the entire fronto-parietal cortex (ipsilaterally) up to the cingulate region, as well as in the ventral thalamic complex and the globus pallidus, i.e. in structures which are not labelled after kainate treatment. Some extent of local damage was observed 1-8 days after the injection; distant from the injection site, we found massive anoxic-ischemic type of damage in the superficial layers of the fronto-parietal cortex, a complete necrosis of the piriform lobe, and neuronal cell loss in the ventral thalamus and several extrapyramidal structures. The full range of limbic damage associated with kainate was never produced by folate. The CA3 region of the hippocampus, most susceptible to kainate, was only mildly affected by folate. These differences between kainate and folate prompted us to re-evaluate the recently reported high affinity of folates for kainic acid membrane binding sites. We found that folic acid competed only very weakly with [3H]kainic acid for binding sites on striatal, cortical, hippocampal, amygdaloid, and cerebellar membranes. It is thus concluded, that folate is not a good candidate for an endogenous kainate-like substance. We propose intracerebral injections of folic acid as a useful tool to study the vulnerability of brain structures to anoxic-ischemic conditions.
Local blood flow, and partial pressures of oxygen and carbon dioxide were directly monitored in the vulnerable region of Ammon's horn (e.g. CA3) of unanaesthetized, freely breathing rats in which epileptic seizures of 120 min duration were induced by parenteral kainic acid. Blood flow was periodically determined by helium clearance. Partial pressures of oxygen and carbon dioxide were simultaneously and continuously measured by means of mass spectrometry, in order to determine if the neuronal damage occurring during the seizures were due to local hypoxia or if blood flow compensated the metabolic demand. During the wet shakes period, a decrease of 35% in the partial pressure of oxygen occurred, concomitant with an increase of 33% in the partial pressure of carbon dioxide and of 330% in local blood flow in Ammon's horn. During the limbic motor seizures, the partial pressure of oxygen increased progressively to twice its baseline value, while the partial pressure of carbon dioxide returned to its baseline value and blood flow underwent a six-fold increase. Thus the seizures produced by kainate do not lead to a mismatch between oxygen supply and blood flow. Our results provide direct evidence that hypoxia cannot be considered responsible for the damage produced by the seizures in CA3. It is concluded that brain damage in CA3 is due to an enhanced neuronal activity associated with the release of a toxic endogenous substance and an excessive rise of intracellular concentration of calcium.
The maturation of the seizure/brain damage syndrome produced by parenteral administration of kainate was studied in the rat. The motor, electrographic and metabolic alterations are described in the present report, the maturation of the pathological abnormalities and of the specific kainate binding sites are described in the two following companion papers. Parenteral kainate produces tonico-clonic seizures until the end of the third week of age when limbic motor signs (wet-dog shakes, facial myoclonia, paw tremor etc.) were first produced. Using the 2-deoxyglucose autoradiographic method, we found that in animals of 3 days of age and until the third week of age, kainate produced a rise in metabolism restricted to the hippocampus and lateral septum. This was paralleled by paroxysmal discharges which were recorded in the hippocampus. Starting from the end of the third week of age approximately--i.e. when the toxin produced limbic motor seizures--there was a rise of labelling in other structures which are part of or closely associated to the limbic system i.e. the amygdaloid complex, the mediodorsal and adjacent thalamic nuclei, piriform, entorhinal and rostral limbic cortices and areas of projection of the fornix. These metabolic maps are thus similar to those seen in adults. Two main conclusions can be drawn from these experiments: kainate activates the hippocampus from a very early age probably by means of specific receptors present in this structure and the limbic syndrome will only be produced by the toxin once the limbic circuitry--including in particular the amygdaloid complex--is activated by the procedure i.e. after the third week of age.
The histopathological sequelae of parenteral administration of kainic acid were investigated in immature rats (3-35 days of age). The brains were fixed 1-14 days after the administration of kainate and the damage evaluated by means of argyrophylic (Fink-Heimer, Gallyas or Nauta-Gygax) and Nissl stains. In animals of less than 18 days of age there was no sign of damage even after 1-2 h of severe tonico-clonic convulsions. Between 18 and 35 days after birth, there was a progressive increase in the severity of the damage, the adult pattern being reached at the latter age. As in adult animals, brain damage was most severe in structures which are part of the limbic system, i.e. the hippocampal formation, lateral septum, amygdaloid complex, claustrum, piriform cortex, etc. In addition to neuronal abnormalities, the following reactions were observed: hypertrophy and swelling of satellite oligodendroglia, proliferation of hypertrophic microglia, proliferation of astroglia and hypertrophy of endothelial cells in the capillary wall. The latter type of change, together with local coagulative necrosis, was almost exclusively restricted to the granular and molecular layers of the fascia dentata. In the hippocampal formation we found a temporal gradient of vulnerability. The earliest and most consistent neuronal alterations were largely restricted to interneurons of the hilar region and to a lesser extent to non-pyramidal neurons of strata oriens and radiatum. The severe necrotic destruction of the pyramidal layer of CA3 is conspicuous at a later age (postnatal day 30-35) and with longer survival times. Our results suggest that: (1) the neurotoxin only induces brain damage once it also causes limbic motor seizures and its associated metabolic activations, notably in the amygdala; (2) the earliest pathological sequelae occur in interneurons of the hilar region and (3) sclerosis of the vulnerable region of the Ammon's horn--the CA3 region--is only obtained once the dentate granules and their mossy fibres are fully operational, thereby reflecting the crucial role of this axonal connection in eliciting hippocampal damage.
The progressive appearance of [3H]kainic acid binding sites with age has been studied in membrane suspensions prepared from various regions of the rat limbic system, and by autoradiography. Binding sites with fast dissociation rate appeared earlier than binding sites with slow dissociation rate. Scatchard analysis demonstrated apparent receptor heterogeneity for both subclasses. High affinity components were detected in the hippocampus as early as 10 days after birth, but in the amygdala + piriform lobe were found only towards the end of the third week, when animals also respond to parenteral kainic acid, for the first time, with limbic seizures accompanied by metabolic activation of the amygdala. Slice autoradiography revealed distinct labelling of the hippocampal CA3 region by postnatal day 10. A comparison with the ontogenesis of the kainic acid-induced seizure-brain damage syndrome suggests a role of high affinity receptors as mediators of metabolic nerve cell activation by kainic acid. However, this receptor interaction per se does not result in neuronal damage to the vulnerable region of the Ammon's horn, which will only occur at an age when also the amygdala is activated by the neurotoxin.
Systemic injections of kainic acid (KA) in adult rats rapidly induce sustained motor seizures preferentially involving the limbic structures and culminating in status epilepticus. The hippocampal formation and amygdala seem to occupy a central position for the onset of paroxysmal discharge and for the manifestation of limbic signs respectively. With long survival periods, the animals spontaneously display limbic motor seizures and a second administration of KA produces more severe effects. The brain damage, found in several limbic structures subsequent to KA-induced seizures, is reminiscent of that seen in human epileptics, and electrographical and metabolic studies (using the 2-deoxyglucose method) reveal that it follows increased neuronal and metabolic activation. The crucial role of the mossy fiber system in the particular vulnerability to KA of the CA3 neurons of Ammon's horn is also suggested by a study of the maturation of the KA-induced seizure and brain damage syndrome.