Model of frequent, recurrent, and spontaneous seizures in the intact mouse hippocampus

Abstract

This study presents a model of chronic, recurrent, spontaneous seizures in the intact isolated hippocampal preparation from mice aged P8-P25. Field activity from the CA1 pyramidal cell layer was recorded and recurrent, spontaneous seizure-like events (SLEs) were observed in the presence of low Mg2+ (0.25 mM) artificial cerebrospinal fluid (ACSF). Hippocampi also showed interictal epileptiform discharges (IEDs) of 0.9-4.2 Hz occurring between seizures. No age-specific differences were found in SLE occurrence (2 SLEs per 10 min, on average), duration, and corresponding frequencies. After long exposure to low Mg2+ ACSF (>3 h), SLEs were completely reversible within minutes with the application of normal (2 mM Mg2+) ACSF. The AMPA antagonist, CNQX, blocked all epileptiform activity, whereas the NMDA antagonist, APV, did not. The gamma-aminobutyric acid (GABA)A antagonist, bicuculline, attenuated and fragmented SLEs, implicating interneurons in SLE generation. The L-type Ca2+ blocker, nifedipine, enhanced epileptiform activity. Analysis of dual site recordings along the septotemporal hippocampus demonstrated that epileptiform activity began first in the temporal pole of the hippocampus, as illustrated by disconnection experiments. Once an SLE had been established, however, the septal hippocampus was sometimes seen to lead the epileptiform activity. The whole hippocampus with intact local circuitry, treated with low Mg2+, provides a realistic model of recurrent spontaneous seizures, which may be used, in normal and genetically modified mice, to study the dynamics of seizures and seizure evolution, as well as the mechanisms of action of anti-epileptic drugs and other therapeutic modalities.

Transition to Seizure: Ictal Discharge Is Preceded by Exhausted Presynaptic GABA Release in the Hippocampal CA3 Region

“…1 A). These events declined in neither amplitude nor duration over the time course of these experiments, consistent with previous studies by Derchansky et al (2004Derchansky et al ( , 2008 in the same seizure model. The recurrent SLEs began after 243 Ϯ 65 s of low-Mg 2ϩ /high-K ϩ ACSF perfusion, with an average duration of 97 Ϯ 13s (n ϭ 5).…”

“…Whole hippocampi were isolated from C57 male black mice (Charles River Laboratory; aged 6 to 12 postnatal days) (Derchansky et al, 2004), which were anesthetized with halothane and decapitated in accordance with the Canadian animal care guidelines. Each brain was quickly removed, hemisectioned, and immersed for 4 -5 min in an ice-old oxygenated (95% O 2 /5% CO 2 ) solution of artificial CSF (ACSF) containing the following (in mM): 123 NaCl, 2.5 KCl, 1.5 CaCl 2 , 2 MgSO 4 , 25 NaHCO 3 , 1.2 NaH 2 PO 4 , and 15 glucose.…”

Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy

“…Here we show they are restricted to electrodes sampling the seizure onset zone. Similar field potentials of larger amplitude precede ictal events in several in vitro models of epilepsy 6,14,[33][34][35] . Moreover, intracranial recordings show PID-like events preceding seizures in multiple focal human epilepsies originating in temporal 17 or extra temporal 36 ; hippocampal 17,18 or neocortical 37 regions, and associated with sclerosis 17,38 , malformation 39 , dysplasia or in macroscopically normal tissue 36 .…”

Effect of nifedipine on hippocampal neuron number in penicillin-induced epileptic rats

“…Contrary to expectations, nifedipine did not influence aminophylline-induced seizures (12), seizures elicited by MES (36) and the protective action of diazepam against PTZ-induced seizures (13). Further, nifedipine decreased topiramate activity in WAG/Rij rats but paradoxically enhanced it in lh/lh mice (41) and increased epileptiform activity in spontaneous seizures in the isolated mouse hippocampus (16). In addition to these, clinical studies have also been performed in epileptic patients to investigate the effects of nifedipine.…”