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

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Abstract
1. Field potential recordings and measurements of the extracellular concentration of free K+ ([K+]o) and Ca2+ ([Ca2+]o) were made during application of 4‐aminopyridine (4‐AP, 50 microM) 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+]o increases to 9.4 +/‐ 3.6 mM (mean +/‐ S.D.) from 3.25 mM baseline (n = 11 slices). [K+]o remained elevated at 5‐6 mM throughout the ictal event. Decreases in [Ca2+]o (from 1.8 mM baseline to 1.3 +/‐ 0.1 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 microM). 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+]o increases (peak values were 8.7 +/‐ 3.2 mM, n = 8), that were blocked, however, by bicuculline methiodide (BMI, 10 microM). 5. The mu‐opioid receptor agonist (D‐Ala2,N‐Me‐Phe4,Gly5‐ol)‐enkephalin (DAGO, 10 microM) which inhibits GABA release from interneurons, prevented the occurrence of both GABA‐mediated synchronous potentials and subsequent ictal discharges (n = 6) as well as the [K+]o elevations. DAGO effects were antagonized by naloxone (10 microM; n = 4). 6. The GABA‐mediated [K+]o elevations changed as a function of age. In hippocampal slices obtained from 11‐ to 17‐day‐old rats, peak values of 10.6 +/‐ 2.0 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 5.2 +/‐ 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+]o elevation undergoes age‐dependent changes, and is instrumental in synchronizing neurons thus initiating prolonged epileptiform discharges.