title: Transition to seizure: ictal discharge is preceded by exhausted presynaptic GABA release in the hippocampal CA3 region.
abstract: How the brain transitions into a seizure is poorly understood. Recurrent seizure-like events (SLEs) in low-Mg2+/ high-K+ perfusate were measured in the CA3 region of the intact mouse hippocampus. The SLE was divided into a "preictal phase," which abruptly turns into a higher frequency "ictal" phase. Blockade of GABA(A) receptors shortened the preictal phase, abolished interictal bursts, and attenuated the slow preictal depolarization, with no effect on the ictal duration, whereas SLEs were blocked by glutamate receptor blockade. In CA3 pyramidal cells and stratum oriens non-fast-spiking and fast-spiking interneurons, recurrent GABAergic IPSCs predominated interictally and during the early preictal phase, synchronous with extracellularly measured recurrent field potentials (FPs). These IPSCs then decreased to zero or reversed polarity by the onset of the higher-frequency ictus. However, postsynaptic muscimol-evoked GABA(A) responses remained intact. Simultaneously, EPSCs synchronous with the FPs markedly increased to a maximum at the ictal onset. The reversal potential of the compound postsynaptic currents (combined simultaneous EPSCs and IPSCs) became markedly depolarized during the preictal phase, whereas the muscimol-evoked GABA(A) reversal potential remained unchanged. During the late preictal phase, interneuronal excitability was high, but IPSCs, evoked by local stimulation, or osmotically by hypertonic sucrose application, were diminished, disappearing at the ictal onset. We conclude that the interictal and early preictal states are dominated by GABAergic activity, with the onset of the ictus heralded by exhaustion of presynaptic release of GABA, and unopposed increased glutamatergic responses.
authors.affiliation: Division of Fundamental Neurobiology, Toronto Western Research Institute, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Zhang J
authors.initials: ZJ
authors.lastname: Zhang
authors.forename: Julius
authors.initials: J
authors.lastname: Koifman
authors.forename: Damian S
authors.initials: DS
authors.lastname: Shin
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Florez
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Taufik A
authors.initials: TA
authors.lastname: Valiante
authors.forename: Peter L
authors.initials: PL
authors.lastname: Carlen
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009118:Muscimol / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000172:deficiency / Q000378:metabolism*
chemical_list: D009118:Muscimol; D005680:gamma-Aminobutyric Acid