Extracellular free potassium and calcium during synchronous activity induced by 4‐aminopyridine in the juvenile rat hippocampus.

Abstract

in hippocampal slices that were obtained from 11-to 32-day-old rats. 2. Spontaneous field potentials recorded under this experimental condition in the CA3 stratum radiatum of slices from rats <23 days old consisted of interictal (duration, 0 2-1 4 s; intervals of occurrence, 0'9-3'4 s) and ictal epileptiform discharges (duration, 5-46 s; intervals of occurrence, 22-259 s) and negative-going potentials that often preceded the onset of ictal discharge. Ictal activity became rare in slices from rats > 25 days old. 3. The negative-going potential (which also corresponded to the ictal discharge onset) was associated with [K+]. increases to 9'4 + 316 mm (mean + S.D.) from 3-25 mm baseline (n = 11 slices).[K+]0 remained elevated at 5-6 mm throughout the ictal event. Decreases in [Ca2+]. (from 1P8 mm baseline to 1'3 + 041 mm, n = 7) were observed during the ictal discharge. 4. Interictal and ictal discharges were abolished by the non-N-methyl-D-aspartate (NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 #M). CNQX and the NMDA receptor antagonist 3-((±)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP) did not influence negative-going potentials or the associated [K+]0 increases (peak values were 8&7 + 3'2 mm, n = 8), that were blocked, however, by bicuculline methiodide (BMI, 10/AM).5. The /S-opioid receptor agonist (D-Ala2,N-Me-Phe4 Gly5-ol)-enkephalin (DAGO, 10 /m) which inhibits GABA release from interneurons, prevented the occurrence of both GABAmediated synchronous potentials and subsequent ictal discharges (n = 6) as well as the [K+]. elevations. DAGO effects were antagonized by naloxone (10 gm; n = 4).6. The GABA-mediated [K+]0 elevations changed as a function of age. In hippocampal slices obtained from 11-to 17-day-old rats, peak values of 10-6 + 210 mm (n = 10) and half-width durations of 8-7 + 1-3 s (n = 7) were observed. In slices obtained from 25-to 32-day-old animals these parameters were 5f2 + 0'5 mm (n = 13) and 4'6 + 1 1 s (n = 4), respectively. 7. This study shows that, in the juvenile rat hippocampus, 4-AP induces a glutamatergic independent synchronous potential that is due to GABA released from inhibitory terminals and is associated with an increase in [K+]O. This [K+]0 elevation undergoes age-dependent changes, and is instrumental in synchronizing neurons thus initiating prolonged epileptiform discharges.

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…As already mentioned, a similar pattern of ictal discharge onset is seen during 4AP treatment in isolated rat hippocampal slices that were obtained from young (11-23 day-old) animals (Avoli, 1990;Avoli et al, 1993Avoli et al, , 1996b. It should be noted that in these studies we found that 4AP discloses ictal discharges in the juvenile but not in the adult hippocampal tissue.…”

“…This "propensity" for ictogenesis may be due to the better ability of the latter to control changes in [K + ] o . In line with this view, the elevations in [K + ] o associated with the slow interictal events recorded during blockade of glutamatergic transmission in the juvenile hippocampal slices are larger than those seen in the adult hippocampus under similar experimental conditions (Avoli et al, 1996b). It should also be emphasized that both experimental (Swann and Brady, 1984;Ben-Ari et al, 1989;Cherubini et al, 1991;Gloveli et al, 1995;Luhmann et al, 2000) and clinical (Aicardi, 1986) studies have provided evidence for dramatic developmental changes in neurotransmitter signaling and, therefore, brain excitability.…”

Models of drug-induced epileptiform synchronization in vitro

“…By employing the in vitro isolated hippocampus from new-born rats Luhmann et al (2000) have shown that 4AP can induce interictal and ictal discharges in the CA3 area as well as that these events can propagate to the entorhinal cortex when animals older than 3 days are used. Remarkably, the pharmacological characteristics of the 4AP-induced epileptiform discharges recorded from the isolated hippocampus were very similar to those identified in the young rat hippocampal slice preparation (Avoli et al, 1996b) since they were abolished by non-NMDA receptor antagonists while they were not significantly influenced by drugs that blocked the NMDA receptor. In contrast, ictal discharges generated by adult limbic areas in brain slices bathed in 4AP containing medium are highly sensitive to both NMDA and non-NMDA glutamatergic receptor antagonists (see for review Avoli and de Curtis, 2011).…”

“…Such ictogenetic "propensity" may reflect developmental changes in neuronal excitability and neurotransmitter signalling as well as in a less efficient ability of the juvenile tissue to control changes in extracellular [K + ]. In line with this view, measurements of the extracellular [K + ] elevations associated with the "slow" 4AP-induced interictal events occurring during blockade of glutamatergic transmission have shown larger values in juvenile than in adult hippocampal slices (Avoli et al, 1996b). However, in line with what originally reported by Galvan et al (1982), ictal-like activity is readily generated in response to 4AP application by neuronal networks in several limbic and extralimbic structures such as the rhinal cortices, the amygdala, and the insular or cingular cortices (Avoli et al, 1996a;Brückner and Heinemann, 2000;Klueva et al, 2003; see for review Avoli and de Curtis, 2011).…”

Effect of γ-ethyl-γ-phenyl-butyrolactone (EFBL), anticonvulsant and hypnotic drug, on mouse brain catecholamine levels

“…Epileptiform discharges were observed during the application of Mg 2+ -free medium, even with the preservation of inhibitory post-synaptic potential caused by GABAA receptor stimulation (8). In addition, it has been determined that selective stimulation of GABAA receptors in the hippocampus causes an increase in extracellular K + , which induces convulsions, even when ionotropic glutamatergic transmission is blocked (9,10). This means that postsynaptic activation of GABAA receptors can also cause membrane depolarization of both interneurons and principal cells in immature cells (11) and some adult long-axoned neurons (12) or interneurons.…”