UMLS:C0344329 - FACTA Search

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Our recent studies on seizure-triggering mechanisms in the kindling model of epilepsy are reviewed. Electroencephalographic (EEG) events during kindling-inducing tetanic stimulation from the site of stimulation were recorded, with an emphasis on EEG suppression and rhythmic synchronous discharge. From electrophysiological and pharmacological analyses of these events, it is hypothesized that activation and subsequent collapse of GABA-A-mediated inhibition is an essential precondition in the initiation of kindled seizures. The excitatory role of NMDA receptors in kindling were also investigated by examining the effects of a noncompetitive antagonist of NMDA receptors (MK-801) on amygdala kindling and hippocampal long-term potentiation (LTP). The results indicate that activation of NMDA receptor complex combined with the collapse of GABA-A-mediated inhibition may be critical for kindling development.
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PMID:Seizure-triggering mechanisms in the kindling model of epilepsy: collapse of GABA-mediated inhibition and activation of NMDA receptors. 255 30

In our previous studies, we hypothesized that activation and subsequent collapse of GABA-mediated inhibition during tetanus is an important seizure-triggering mechanism in the kindled epileptogenic focus. To examine this hypothesis, in the present study, we investigated the effects of pharmacological manipulations of the kindled amygdala with several drugs, and measured the kindled seizures as well as the EEG events during tetanus. The results obtained were: (i) The selective GABA-A agonist, muscimol (1 and 5 nM/1 microliter), suppressed kindled seizures in a dose-dependent fashion, and the 5 nM muscimol significantly prolonged EEG suppression and reduced the number of oscillations in the subsequent rhythmic synchronous discharge. Similar effects followed systemic injection of diazepam (2 mg/kg). (ii) The selective GABA-B agonist, baclofen (5 nM), had no effect on kindled seizures nor on the EEG events during tetanus. (iii) The NMDA antagonist, 2-amino-5-phosphonovaleric acid (80 nM), significantly reduced the afterdischarge duration and significantly delayed the appearance of the rhythmic synchronous discharge. However, these effects were not observed immediately, but 24 to 72 h after microinjection. (iv) The muscarinic cholinergic antagonist, atropine (40 and 80 nM), suppressed kindled seizures in a dose-dependent fashion, but the atropine caused marked synchronous discharge both in the awake resting EEG and during tetanic stimulation. We conclude that the GABA-A system, including the benzodiazepine system, is more involved in the seizure-triggering mechanism of amygdala kindling than the GABA-B system, that there is an interaction between the GABA-A and NMDA system, and that the cholinergic participation is independent of the primary seizure-triggering mechanisms.
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PMID:Kindling-induced changes in EEG recorded during stimulation from the site of stimulation. III. Direct pharmacological manipulations of the kindled amygdala. 288 27

Gamma-aminobutyric acid A (GABAA) receptors are the principal mediators of synaptic inhibition, and yet when intensely activated, dendritic GABAA receptors excite rather than inhibit neurons. The membrane depolarization mediated by GABAA receptors is a result of the differential, activity-dependent collapse of the opposing concentration gradients of chloride and bicarbonate, the anions that permeate the GABAA ionophore. Because this depolarization diminishes the voltage-dependent block of the N-methyl-D-aspartate (NMDA) receptor by magnesium, the activity-dependent depolarization mediated by GABA is sufficient to account for frequency modulation of synaptic NMDA receptor activation. Anionic gradient shifts may represent a mechanism whereby the rate and coherence of synaptic activity determine whether dendritic GABAA receptor activation is excitatory or inhibitory.
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PMID:Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. 763 14

The effect of nitric oxide donors and L-arginine on the uptake of GABA was studied in synaptosomes purified from rat brain. The neurotransmitter uptake was significantly reduced by S-nitrosoacetylpenicillamine and by sodium nitroprusside, although in this case to a lesser extent. A slight inhibitory effect was found preincubating rat brain synaptosomes with 1 mM L-arginine as well. The S-nitrosoacetylpenicillamine effect gradually disappeared with decomposition of the substance by exposure to light. The nitric oxide effect appears to be mainly due to a decrease in the V for synaptosomal GABA uptake and seems to be related to a partial collapse of nerve endings ionic gradients. Functionally, it could result over time in a reduced availability of GABA at the synapses involved.
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PMID:Effect of nitric oxide donors on GABA uptake by rat brain synaptosomes. 935 19

Local application of GABA to rat cerebral cortical neurons in brain slices elicited biphasic responses mediated via GABAA receptors. The fast component of the response, which was most apparent with somatic application of GABA, was hyperpolarizing at the normal resting membrane potential (GABAh response). The slower component could be elicited by GABA application to nearly all regions of the cell, and was depolarizing at the resting membrane potential (GABAd response). The reversal potential of evoked IPSCs recorded with whole-cell patch electrodes (-68 mV) was comparable to the reversal potential of the GABAh response (-69 mV), and was significantly different from the reversal potential of the GABAd response (-56 mV). The GABAd response was more sensitive to enhancement by pentobarbital and more readily antagonized by both bicuculline and picrotoxin than the GABAh response. Recording in bicarbonate-free buffer changed the reversal potential of the GABAd response significantly, but had no effect on the GABAh response. In contrast, superfusion with ethanol significantly enhanced the GABAh response, while having no effect on the GABAd component. Although a localized collapse of the Cl- gradient, which has been proposed to underlie the GABAd response, could explain the greater sensitivity of the GABAd response to pentobarbital and the GABAA antagonists, this could not account for the greater sensitivity of the GABAh response to ethanol. Differences in GABAA receptor subunit composition may result in the expression of dendritic and somatic GABAA receptors that have different kinetics, reversal potentials, and sensitivity to pharmacological agents, including ethanol.
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PMID:Ethanol selectively enhances the hyperpolarizing component of neocortical neuronal responses to locally applied GABA. 968 36

Oxytocin, the most powerful uterotonic agent known, is released from the pituitary gland in large amounts during parturition in all placental mammals studied so far, including humans. Although parturition can proceed in its absence, oxytocin is thought to play an important role (see Russell & Leng, 1998). In the rat, pregnancy normally lasts for 21 days. About 24 h before the pups are born, increased production of prostaglandins by the uterus induces luteolysis, and ovarian progesterone production falls dramatically. This fall is an essential prelude to parturition; if prevented, then the rat pups will remain unborn. The fall leads to a further increase in prostaglandin production, and, directly or indirectly, to a host of changes that prepare the uterus and birth canal for parturition. In the last few hours of pregnancy, oxytocin receptors appear in high concentrations in the uterus, and establish a positive-feedback loop between the uterus and the hypothalamic oxytocin system. Uterine contractions, triggered by prostaglandins, excite the oxytocin cells, and oxytocin release triggers further prostaglandin production and further uterine contraction. Thus progesterone plays a critical role in the timing of parturition through its peripheral actions (see Leng & Brown, 1997). A paper in this issue of The Journal of Physiology (Brussaard et al. 1999) suggests that actions of progesterone at the oxytocin cells in the hypothalamus may also be important for parturition. Classically, progesterone acts through specific intracellular receptors to regulate gene expression. However, metabolites of progesterone can also have membrane actions, and in particular, allopregnanolone can act at GABAA receptors to potentiate the actions of GABA, depending upon the particular subunit composition of the receptor. GABA is an important neurotransmitter for oxytocin cells about 45 % of all synapses onto them contain GABA, and the total number of GABA synapses in the supraoptic nucleus is substantially higher in lactating animals than in virgins (El Majdoubi et al. 1997). The GABA innervation appears to play a role in patterning the pulsatile discharge of oxytocin cells that is observed both during parturition and during suckling-induced reflex milk ejection (Moos, 1995; Voisin et al. 1995). Brussaard et al. (1999) recorded GABAA receptor-mediated spontaneous monoquantal inhibitory postsynaptic currents (sIPSCs) from rat supraoptic neurones in hypothalamic slices in vitro. They found a higher incidence of sIPSCs in pregnant rats than in virgin rats, consistent with the observations of an increase in the density of GABA-containing synaptic boutons. Importantly, the sIPSCs were markedly prolonged in the presence of allopregnanolone. Taking into account the frequency and amplitude of sIPSCs, the action of allopregnanolone and the hypertrophy of oxytocin neurones in lactation (reflected in increased capacitance), Brussaard et al. (1999) inferred that the effective GABAA receptor-mediated synaptic current density was much greater in pregnant rats than in virgin or lactating rats. Thus the collapse of progesterone production at term may abruptly reduce the effectiveness of GABA inhibition, and thereby enhance the excitability of oxytocin cells. Clearly this may be important during parturition, but the effect may not persist for long. Indeed, within a day the duration of sIPSCs is significantly longer in the absence of allopregnanolone, which now has no significant effect. This seems to be due to a rapid switch in the types of a subunits inserted into the GABAA receptors. By mid-lactation, a massive change in expression of GABAA receptor subunit mRNAs is apparent. With competitive polymerase chain reaction Brussaard and colleagues found that, while the expression of both a1 and a2 subunit mRNAs was increased, the ratio of a1 : a2 subunit mRNA expression was changed 8-fold in favour of a2 subunit mRNA. (ABSTRACT TRUNCATED)
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PMID:Coming to term with GABA 1008 58

We used northern and western blotting to measure the quantity of glutamate and GABA transporters mRNA and their proteins within the hippocampal tissue of rats with epileptogenesis. Chronic seizures were induced by amygdalar injection of kainic acid 60 days before death. We found that expression of the mRNA and protein of the glial glutamate transporters GLAST and GLT-1 were down-regulated in the kainic acid-administered group. In contrast, EAAC-1 and GAT-3 mRNA and their proteins were increased, while GAT-1 mRNA and protein were not changed. We performed in vivo microdialysis in the freely moving state. During the interictal state, the extracellular glutamate concentration was increased, whereas the GABA level was decreased in the kainic acid group. Following potassium-induced depolarization, glutamate overflow was higher and the recovery time to the basal release was prolonged in the kainic acid group relative to controls. Our data suggest that epileptogenesis in rats with kainic acid-induced chronic seizures is associated with the collapse of extracellular glutamate regulation caused by both molecular down-regulation and functional failure of glutamate transport.
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PMID:Collapse of extracellular glutamate regulation during epileptogenesis: down-regulation and functional failure of glutamate transporter function in rats with chronic seizures induced by kainic acid. 1115 61

GABA, the main inhibitory neurotransmitter in the brain, elicits a hyperpolarizing response by activation of the GABA(A)-receptor/chloride-channel complex under conditions of normal Cl(-) homeostasis. Thus the pathogenesis of epilepsy could involve an impairment of GABA(A)-receptor-mediated inhibition due to a collapse of the Cl(-) gradient. We examined the expression patterns of Cl(-) transporters and a Cl(-) channel in a rat amygdala-kindling model. Activity-dependent increases were observed in the mRNA for NKCC1, an inwardly-directed Cl(-) transporter, in the piriform cortex. This suggests that an increase in [Cl(-)](i) and a resultant reduction in GABAergic inhibition may occur in the kindled piriform cortex.
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PMID:Amygdala kindling induces upregulation of mRNA for NKCC1, a Na(+), K(+)-2Cl(-) cotransporter, in the rat piriform cortex. 1235 37

High levels of Silver (Ag), Barium (Ba) and Strontium (Sr) and low levels of copper (Cu) have been measured in the antlers, soils and pastures of the deer that are thriving in the chronic wasting disease (CWD) cluster zones in North America in relation to the areas where CWD and other transmissible spongiform encephalopathies (TSEs) have not been reported. The elevations of Ag, Ba and Sr were thought to originate from both natural geochemical and artificial pollutant sources--stemming from the common practise of aerial spraying with 'cloud seeding' Ag or Ba crystal nuclei for rain making in these drought prone areas of North America, the atmospheric spraying with Ba based aerosols for enhancing/refracting radar and radio signal communications as well as the spreading of waste Ba drilling mud from the local oil/gas well industry across pastureland. These metals have subsequently bioconcentrated up the foodchain and into the mammals who are dependent upon the local Cu deficient ecosystems. A dual eco-prerequisite theory is proposed on the aetiology of TSEs which is based upon an Ag, Ba, Sr or Mn replacement binding at the vacant Cu/Zn domains on the cellular prion protein (PrP)/sulphated proteoglycan molecules which impairs the capacities of the brain to protect itself against incoming shockbursts of sound and light energy. Ag/Ba/Sr chelation of free sulphur within the biosystem inhibits the viable synthesis of the sulphur dependent proteoglycans, which results in the overall collapse of the Cu mediated conduction of electric signals along the PrP-proteoglycan signalling pathways; ultimately disrupting GABA type inhibitory currents at the synapses/end plates of the auditory/circadian regulated circuitry, as well as disrupting proteoglycan co-regulation of the growth factor signalling systems which maintain the structural integrity of the nervous system. The resulting Ag, Ba, Sr or Mn based compounds seed piezoelectric crystals which incorporate PrP and ferritin into their structure. These ferrimagnetically ordered crystals multireplicate and choke up the PrP-proteoglycan conduits of electrical conduction throughout the CNS. The second stage of pathogenesis comes into play when the pressure energy from incoming shock bursts of low frequency acoustic waves from low fly jets, explosions, earthquakes, etc. (a key eco-characteristic of TSE cluster environments) are absorbed by the rogue 'piezoelectric' crystals, which duly convert the mechanical pressure energy into an electrical energy which accumulates in the crystal-PrP-ferritin aggregates (the fibrils) until a point of 'saturation polarization' is reached. Magnetic fields are generated on the crystal surface, which initiate chain reactions of deleterious free radical mediated spongiform neurodegeneration in surrounding tissues. Since Ag, Ba, Sr or Mn based piezoelectric crystals are heat resistant and carry a magnetic field inducing pathogenic capacity, it is proposed that these ferroelectric crystal pollutants represent the transmissible, pathogenic agents that initiate TSE.
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PMID:Elevated silver, barium and strontium in antlers, vegetation and soils sourced from CWD cluster areas: do Ag/Ba/Sr piezoelectric crystals represent the transmissible pathogenic agent in TSEs? 1523 78

Zinc is concentrated in the hippocampus, particularly in the mossy fiber axons of the dentate gyrus, and has been hypothesized to be important in neurodegeneration and epilepsy. Previous studies have suggested that activity-dependent release of zinc from reorganized mossy fibers leads to collapse of granule-cell inhibition. Synaptically released zinc has been proposed to depress the function of the new "epileptic" GABA(A) receptors, which have subunits that are zinc-sensitive. Recent experiments by Molnar and Nadler have replicated the previous data, and further tested this hypothesis. Their work suggests that activated mossy fibers in hippocampal slices do not release adequate zinc to depress GABA(A) receptor function at nearby inhibitory synapses. These studies point to the complexity of this hypothesis, particularly in regard to zinc release in vitro versus in vivo and the diffusion of zinc in the extracellular space.
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PMID:Zinc and Epileptogenesis. 1530 93

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