title: Neuronal mechanisms of the anoxia-induced network oscillations in the rat hippocampus in vitro.
abstract: 1. A spindle of fast network oscillations precedes the ischaemia-induced rapid depolarisation in the rat hippocampus in vivo. However, this oscillatory pattern could not be reproduced in slices and the underlying mechanisms remain poorly understood. We have found that anoxia-induced network oscillations (ANOs, 20-40 Hz, lasting for 1-2 min) can be reproduced in the intact hippocampi of postnatal day P7-10 rats in vitro, and we have examined the underlying mechanisms using whole-cell and extracellular field potential recordings in a CA3 pyramidal layer. 2. ANOs were generated at the beginning of the anoxic depolarisation, when pyramidal cells depolarised to subthreshold values. Maximal power of the ANOs was attained when pyramidal cells depolarised to -56 mV; depolarisation above -47 mV resulted in a depolarisation block of pyramidal cells and a waning of ANOs. 3. A multiple unit activity in extracellular field recordings was phase locked to the negative and ascending phases of ANOs. Pyramidal cells recorded in current-clamp mode generated action potentials with an average probability of about 0.05 per cycle. The AMPA receptor-mediated EPSCs and the GABA receptor-mediated IPSCs in CA3 pyramidal cells were also phase locked with ANOs. 4. ANOs were prevented by tetrodotoxin and glutamate receptor antagonists CNQX and APV, and were slowed down by the allosteric GABA(A) receptor modulator diazepam. In the presence of the GABA(A) receptor antagonist bicuculline, ANOs were transformed to epileptiform discharges. 5. In the presence of the A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), the anoxia induced an epileptiform activity and no ANOs were observed. 6. In normoxic conditions, a rise of extracellular potassium to 10 mM induced an epileptiform activity. Increasing extracellular potassium in conjunction with a bath application of the adenosine A1 receptor agonist cyclopentyladenosine induced oscillations similar to ANOs. 7. Multisite recordings along the septo-temporal hippocampal axis revealed that ANOs and anoxic depolarisation originate in the temporal part, and propagate towards the septal pole at a speed of 1.9 mm x min(-1). 8. ANOs were observed starting from P7, i.e. at a developmental stage when the effects of GABA change from depolarisation to hyperpolarisation. 9. These results suggest that the synchronisation of anoxia-induced oscillations relies on synaptic mechanisms; that the inhibition by GABA and adenosine sets the tune for a generation of oscillations and prevents an epileptiform activity; and that a synchronous GABAergic inhibition is instrumental in a phase locking neuronal activity similarly to other types of oscillatory activities in the gamma frequency range.
authors.affiliation: INMED-INSERM U29, Avenue de Luminy, B.P. 13 13273 Marseille Cedex 09, France.
authors.forename: V
authors.initials: V
authors.lastname: Dzhala
authors.forename: I
authors.initials: I
authors.lastname: Khalilov
authors.forename: Y
authors.initials: Y
authors.lastname: Ben-Ari
authors.forename: R
authors.initials: R
authors.lastname: Khazipov
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000503:physiopathology*; D002534:Hypoxia, Brain / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010507:Periodicity; D011188:Potassium / Q000494:pharmacology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D000779:Anesthetics, Local; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018757:GABA Modulators; D014970:Xanthines; C048599:N(6)-cyclopentyladenosine; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D003975:Diazepam; D011188:Potassium; D001640:Bicuculline