Calcium-activated afterhyperpolarizations regulate synchronization and timing of epileptiform bursts in hippocampal CA3 pyramidal neurons.
Calcium-activated potassium conductances regulate neuronal excitability, but their role in epileptogenesis remains elusive. We investigated in rat CA3 pyramidal neurons the contribution of the Ca(2+)-activated K(+)-mediated afterhyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg(2+)-free Ringer. Recurring spike bursts terminated by prolonged AHPs were generated. Burst synchronization between CA3 pyramidal neurons in paired recordings typified this interictal-like activity. A downregulation of the medium afterhyperpolarization (mAHP) paralleled the emergence of the interictal-like activity. When the mAHP was reduced or enhanced by apamin and EBIO bursts induced by 4-AP were increased or blocked, respectively. Inhibition of the slow afterhyperpolarization (sAHP) with carbachol, t-ACPD, or isoproterenol increased bursting frequency and disrupted burst regularity and synchronization between pyramidal neuron pairs. In contrast, enhancing the sAHP by intracellular dialysis with KMeSO(4) reduced burst frequency. Block of GABA(A-B) inhibitions did not modify the abnormal activity. We describe novel cellular mechanisms where 1) the inhibition of the mAHP plays an essential role in the genesis and regulation of the bursting activity by reducing negative feedback, 2) the sAHP sets the interburst interval by decreasing excitability, and 3) bursting was synchronized by excitatory synaptic interactions that increased in advance and during bursts and decreased throughout the subsequent sAHP. These cellular mechanisms are active in the CA3 region, where epileptiform activity is initiated, and cooperatively regulate the timing of the synchronized rhythmic interictal-like network activity.
Fernández de Sevilla
David
D
Instituto Cajal, Consejo Superior de Investigaciones Científicas, Av. Dr. Arce 37, 28002 Madrid, Spain.
Garduño
Julieta
J
Galván
Emilio
E
Buño
Washington
W
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002586:Cesium / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004558:Electric Stimulation; D004594:Electrophysiology; D004827:Epilepsy / Q000503:physiopathology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013826:Theta Rhythm / Q000187:drug effects
D002614:Chelating Agents; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D002586:Cesium; D015761:4-Aminopyridine