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E F Sperber

Publications and source records attributed to E F Sperber.

At least 37 records · Page 2Linked to original sources
PubMed1995

Ontogeny and topography of seizure regulation by the substantia nigra.

The substantia nigra pars reticulata (SNR) is a structure involved in the control of seizures, and its effects on seizures are age-dependent. GABAergic transmission in the SNR, mediated by GABAA receptors, influences seizure susceptibility. We have found that in the adult SNR there may be at least two segregated GABAA-sensitive SNR projection networks involved in regulating the SNR effects on seizures, perhaps reflecting the existence of an anticonvulsant and a proconvulsant network. The two networks with opposing effects on seizures originate from two topographically distinct regions. The anterior-medial region of the SNR is associated with anticonvulsant effects, whereas the posterior-dorsal region of the SNR is associated with proconvulsant effects. To explain ontogenic differences in the SNR effects on seizures, we hypothesize that the two functionally segregated networks which influence the expression of seizures may become segregated with maturation. The increased seizure susceptibility of rat pups may be due, in part, to delayed development of this anterior-medial SNR anticonvulsant network.

Age Factors↗
PubMed1995

Age-related differences in the effects of GABAA agonists microinjected into rat substantia nigra: pro- and anticonvulsant actions.

GABAergic transmission in the substantia nigra pars reticulata (SNR) has an important role in the control of experimental seizures. In the flurothyl seizure model, SNR microinjection of the selective GABAA receptor agonist muscimol results in a biphasic dose-response curve in adults: Intermediate doses are anticonvulsant, but high doses have proconvulsant effects. Another GABAA agonist, THIP (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol), also produces anticonvulsant effects at lower doses, whereas higher doses tend to produce a proconvulsant effect. In 16-day-old rat pups, no anticonvulsant but only proconvulsant effects of muscimol occur, and at lower doses than in adults. These data suggest that the immature SNR is significantly more sensitive to the proconvulsant effects of GABAA receptor agonists than is the SNR of adults. We hypothesize that the age-related differences in nigral GABAergic response may be due to ontogenic changes in GABAA-sensitive neuronal circuits in the SNR.

Age Factors↗
PubMed1994

Maturation and segregation of brain networks that modify seizures.

The mature brain is less susceptible to seizures than the immature brain. We demonstrate that in the mature substantia nigra (SN) there are two topographically discrete GABAA-sensitive regions which differ in the amount of mRNA expression of the GABAA receptor alpha 1 subunit. These two regions mediate separate anticonvulsant and proconvulsant effects and use divergent projection networks. By contrast, in the immature SN there is no special topography of mRNA expression of the alpha 1 subunit and only the proconvulsant network is present. The decreased seizure susceptibility of the mature brain may be related to postnatal segregation of GABAA-sensitive networks.

Animals↗
PubMed1994

The development of epilepsy in the paediatric brain.

The immature central nervous system (CNS) is more susceptible to the development of seizures than its adult counterpart. Developmental studies of experimental seizures have suggested that young animals have unique behavioural seizure patterns, including the presence of bilateral, though asymmetric, convulsions. There are differences in the mechanisms responsible for the generation of seizures, propagation patterns and seizure arrest and recurrences. These differences are due to local factors as well as factors that affect neural systems consisting of long neuronal circuits. The substantia nigra, a site involved in the control of seizures, will be used as an example to demonstrate how evolving neurobiological processes modulates the suppression or exacerbation of seizures with age. Evidence will also be presented indicating that early in life, seizures may not produce hippocampal damage. An understanding of the age-related differences is important for the development of rational approaches to treating seizures and their consequences.

Age Factors↗
PubMed1994

Kainate-induced status epilepticus alters glutamate and GABAA receptor gene expression in adult rat hippocampus: an in situ hybridization study.

In adult rats, intraperitoneal administration of kainic acid, a glutamic acid analog and potent neurotoxin, induces persistent seizure activity that results in electrographic alterations and neuropathology that closely resemble human temporal lobe epilepsy. We used in situ hybridization to identify regions of altered glutamate and GABAA receptor gene expression following kainate-induced status epilepticus. In the CA3/CA4 area, the hippocampal region most vulnerable to neurodegeneration after kainate acid treatment, expression of GluR2 (the AMPA/kainate receptor subunit that limits Ca2+ permeability) and GluR3 was decreased markedly at 12 and 24 hr, times preceding neurodegeneration. These findings raise the possibility that increased formation of Ca(2+)-permeable AMPA/kainate receptors in the CA3/CA4 area may enhance glutamate pathogenicity. Expression of the GABAA alpha 1, subunit was also reduced, indicating a possible decrease in inhibitory transmission, which would also enhance excitotoxicity. GluR1 and NR1 expression was not significantly changed. In the dentate gyrus, a region resistant to neurodegeneration, concomitant increases in GluR2 and GluR3 expression were observed; GluR1, NR1, and GABAA alpha 1 mRNAs were not detectably altered. Analysis of emulsion-dipped sections revealed that the changes in GluR2, GluR3, and GABAA alpha 1 expression represented changes in mRNA content per neuron and were specific to pyramidal cells of the CA3/CA4 area and to granule cells of the dentate gyrus. These findings indicate that kainate seizures modify hippocampal glutamate and GABAA receptor expression in a cell-specific manner. Timing of the changes in glutamate and GABAA receptor mRNAs indicates that these changes may play a causal role in hippocampal neuronal cell loss following kainate-induced seizures.

Animals↗
PubMed1993

The influence of thalamic GABA transmission on the susceptibility of adult rats to flurothyl induced seizures.

There is considerable evidence that thalamic nuclei are involved in the propagation and regulation of seizures. In the present study, we investigated the possible role in seizure mechanisms of GABAergic transmission in two thalamic nuclei, the posterior nucleus (PO) and the ventromedial nucleus (VM). Several GABAergic drugs were bilaterally microinfused into PO or VM of adult rats via chronically implanted cannulae, before testing the rats' susceptibility to seizures induced by flurothyl. In PO, infusions of the GABA elevating agent gamma-vinyl-GABA (20 micrograms) or of the GABAA receptor agonist muscimol (100 ng) suppressed both clonic and tonic seizures. Infusions into PO of the GABAA receptor antagonist bicuculline (100 ng) facilitated both these seizure types. Administration of the GABAB receptor agonist baclofen (200 ng) also suppressed clonic seizure susceptibility. Drug infusions into VM, however, did not significantly modify the susceptibility to seizures. These findings lead us to conclude that GABAergic transmission in the vicinity of the PO, but perhaps not in VM, affects flurothyl seizure susceptibility. We hypothesize that GABA synapses in PO may be part of a seizure propagation or control circuit including striatum, substantia nigra, and superior colliculus.

Aminocaproates↗
PubMed1992

The proconvulsant effect of nigral infusions of THIP on flurothyl-induced seizures in rat pups.

The substantia nigra gamma-aminobutyric acid (GABA) system is crucial for seizure control. Our previous work indicates that in 16-day-old rat pups, nigral administration of the GABAA receptor agonist muscimol facilitates flurothyl-induced seizures, whereas it suppresses seizures in adult rats. To determine whether the proconvulsant effect of muscimol in rat pups may be mediated by nigral GABAA receptors, in the present study we applied a selective GABAA receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). Bilateral nigral infusions of THIP (500 or 700 ng) significantly decreased the thresholds for flurothyl seizures in a dose-dependent fashion. Doses of 350 ng or less did not significantly modify the susceptibility to seizures. An anticonvulsant action of THIP could not be detected at any dose. Administration of an effective THIP dose (500 ng) 2 mm dorsal to the SNR had no influence on seizures. These findings suggest that in rat pups the proconvulsant effect of nigral GABAA receptor agonists may be attributed to unique pharmacologic characteristics of GABAA receptors during development.

Animals↗
PubMed1992

Kindling in developing animals: interactions between ipsilateral foci.

In adult rats, concurrent kindling of two limbic sites, alternating stimulation to each site, often results in the retarding of kindling at one or both sites. This inhibitory interaction between two limbic kindling foci is termed kindling antagonism and occurs irrespective of whether the sites are contralateral or ipsilateral. We have previously shown that kindling antagonism does not occur when 16- to 17-day-old rat pups are concurrently kindled in the hippocampus and contralateral amygdala or between the two amygdalae. In this study, adult and 16- to 17-day-old rats were concurrently kindled in the hippocampus and ipsilateral amygdala to determine if the local intrahemispheric mechanisms suppressing multiple kindled foci are age-dependent. Kindling antagonism occurred in 7 out of 10 adult rats. In contrast, in rat pups, kindling development was not suppressed. Concurrent kindling of the two limbic sites enhanced the development of severe seizures. Two 16- to 17-day-old rats receiving alternating stimulations exhibited spontaneous seizures. The age-specific failure of both inter- and intrahemispheric mechanisms to suppress the development of multiple kindling foci may explain the high incidence of multifocal seizures in the immature CNS.

Amygdala↗
PubMed1991

Effects of substantia nigra gamma-vinyl-GABA infusions on flurothyl seizures in adult rats.

There is evidence implicating the nigral gamma-aminobutyric acid (GABA) system in the control of seizures. Our previous studies have demonstrated that, in rat pups, intranigrally infused gamma-vinyl-GABA (GVG, 5-20 micrograms) strongly suppresses flurothyl-induced tonic but not clonic seizures. Furthermore, nigral infusions of bicuculline or muscimol abolish the anticonvulsant effect of GVG. In this study, we report that in adult rats bilateral infusions of GVG (20 micrograms) into the substantia nigra pars reticulata (SNR) significantly elevated the thresholds for both clonic and tonic seizures induced by flurothyl. Lower doses (5 and 10 micrograms) did not significantly protect adult rats against seizures, but there was a significant effect of GVG dose. Unilateral infusion of GVG (20 micrograms) in the SNR did not alter the thresholds for flurothyl-induced seizures. Intranigral infusions of bicuculline following pretreatment with GVG abolished the protective effect of GVG on flurothyl-induced seizures, indicating that the anticonvulsant effect of GVG is most likely mediated by the nigral GABAA receptor. Intranigral administration of muscimol after GVG pretreatment significantly suppressed flurothyl-induced seizures, but the combined effect of the two drugs was not as strong as that of GVG alone. The data suggest that GVG protects adult rats against flurothyl-induced seizures. In adults, however, the dose of GVG required to protect against both clonic and tonic seizures is higher than that needed in rat pup SNR.

Aminocaproates↗
PubMed1991

Resistance of the immature hippocampus to seizure-induced synaptic reorganization.

Temporal lobe epilepsy is a common form of epilepsy in human adults and is associated with a unique pattern of damage in the hippocampus. The damage includes cell loss of the CA3 and CA4 areas and synaptic growth (sprouting) of mossy fibers in the supragranular layer of the dentate gyrus. Experimental evidence indicates that in adult rats the excitatory amino acid, kainic acid, induces a similar pattern of changes in hippocampal circuitry associated with alterations in perforant path excitation and inhibition. It has been suggested that, in humans, this type of damage may be a result of seizures early in life. In this study we examined the effects of kainic acid-induced status epilepticus on synaptic reorganization and paired-pulse electrophysiology in developing rats and adults. Kainic acid induced more severe seizures in 15-day-old rat pups than in adults. In contrast to adult rats, these seizures did not produce CA3/CA4 neuronal loss, mossy fiber sprouting or changes in paired-pulse excitation or inhibition in the hippocampus of rat pups tested 2-4 weeks after status epilepticus. Our results provide evidence that the immature hippocampus may be more resistant to seizure-induced changes than the mature hippocampus.

Animals↗
PubMed1991

Is the anticonvulsant effect of substantia nigra infusion of gamma-vinyl-GABA (GVG) mediated by the GABAA receptor in rat pups?

The substantia nigra GABAergic system is considered important for the modification of seizures. Our previous studies have shown that, in rat pups, nigral infusions of baclofen suppressed flurothyl-induced seizures. In the present study, we determined, in rat pups, the effect of nigral infusions of gamma-vinyl-GABA (GVG) on clonic-tonic seizures induced by flurothyl, generated a dose-response curve of the GVG effect and investigated the possible role of the nigral GABAA receptor in mediating the GVG effect. Bilateral nigral infusions of GVG profoundly suppressed flurothyl-induced tonic seizures in a dose-dependent fashion. Flurothyl-induced clonic seizures were not modified. The lowest effective dose of nigral GVG administration was 5 micrograms/0.25 microliter per site. Nigral infusions of GVG at doses greater than 10 micrograms/0.25 microliter induced sedation as well. Infusions of GVG, 2 mm dorsal to the substantia nigra, did not alter seizure latencies. Bilateral nigral infusions of bicuculline, a specific GABAA receptor antagonist, reduced the protective potency of GVG against flurothyl-induced seizures. Nigrally administered muscimol, a GABAA receptor agonist, also attenuated the anticonvulsant effect of GVG. These findings suggest that the optimal dose of nigrally infused GVG against flurothyl-induced seizures is in the range of 5-10 micrograms/0.25 microliter and that GVG may be more efficient as an anticonvulsant for the treatment of tonic seizures in developing animals. The anticonvulsant effect of GVG may, in part, involve the nigral GABAA receptor. The data, together with the previous experiments, indicate that both nigral GABAA and GABAB receptors may play a role in the regulation of seizures in rat pups.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminocaproates↗
PubMed1990

Kindling in developing animals: expression of severe seizures and enhanced development of bilateral foci.

In adult rats, alternating stimulations between two limbic sites can result in one site kindling normally, while the other is retarded in an early non-generalized kindling stage. This phenomenon has been named kindling antagonism. In this report, we present data indicating that kindling antagonism does not occur in 16-day-old rats. Instead, 16-day-old rats receiving alternating stimulations in the amygdala and hippocampus develop progressively more severe seizures. Kindling with alternate stimulations is elicited at a much faster rate at the two foci compared to kindling from a single site, either the hippocampus or amygdala. All groups develop generalized seizures including seizure stages 6 and 7, consisting of wild jumping, running with vocalizations and tonus. These seizures appear after relatively few stimulations in the pup, in comparison to the adult. The results indicate that the immature brain is less able to suppress the generalization of seizures than the adult. The age-specific enhanced development of bilateral foci may be due to underdeveloped inhibitory systems and may underlie the propensity of the immature CNS to develop multifocal seizures.

Amygdala↗
PubMed1989

Evidence for the involvement of nigral GABAB receptors in seizures of rat pups.

The substantia nigra GABA-sensitive system is important for the modification of seizures. In adult rats, nigral infusions of baclofen (GABAB agonist) had no effect on flurothyl seizures. This suggests that the nigral GABAB receptor system may not be involved in the mediation of flurothyl seizures in this age group. The present study examines whether the nigral GABAB receptor is involved in the modification of flurothyl seizures in rat pups and whether systemic infusions of baclofen could alter their seizure susceptibility. Baclofen (50-200 ng/0.25 microliters) was intranigrally administered to 16-day-old rat pups which were then exposed to flurothyl seizures. Results indicated that intranigral infusions of baclofen (100 and 200 ng/0.25 microliters) protected the rat pups against seizures. Systemic injections of baclofen also protected pups from flurothyl seizures suggesting that it may be worthwhile to examine baclofen as a potential antiepileptic drug in children.

Age Factors↗