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 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.
Avoli
M
M
Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Louvel
J
J
Kurcewicz
I
I
Pumain
R
R
Barbarosie
M
M
D015761:4-Aminopyridine / Q000494:pharmacology*; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000375:Aging / Q000378:metabolism / Q000502:physiology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017450:Receptors, Opioid, mu / Q000187:drug effects
D000700:Analgesics; D004745:Enkephalins; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D015761:4-Aminopyridine; D011188:Potassium; D002118:Calcium