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

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 mu M) 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 mu 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+](o) increases (peak values were 8.7 +/- 3.2 mM, n = 8), that were blocked, however, by bicuculline methiodide (BMI, 10 mu M). 5. The mu-opioid receptor agonist (D-Ala(2),N-Me-Phe(4),Gly(5)-ol)-enkephalin (DAGO, 10 mu M) 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 mu M; 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 tl:at 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.