A guinea pig model of mesial temporal lobe epilepsy following nonconvulsive status epilepticus induced by unilateral intrahippocampal injection of kainic acid

Abstract

SUMMARYPurpose: Models of temporal lobe epilepsy are commonly utilized to study focal epileptogenesis and ictogenesis. The criteria that define animal models representative of human mesial temporal lobe may vary in different laboratories. We describe herein a focal epilepsy model of mesial temporal (hippocampal) origin that relies on the analysis of interictal and ictal electroencephalography (EEG) patterns and on their correlation with seizure symptoms and neuropathologic findings. The study is based on guinea pigs, a species seldom utilized to develop chronic epilepsy models. Methods: Young adult guinea pigs were bilaterally implanted under isoflurane anesthesia with epidural electrodes over somatosensory cortex and depth electrodes in CA1 hippocampal region. A stainless steel guide cannula was positioned unilaterally in the right dorsal hippocampus to inject 1 ll of 0.9% NaCl solution containing 1 lg kainic acid (KA). One week after surgery, continuous 24 h/day video-EEG monitoring was performed 48 h before and every other week after KA injection, for no <1 month. EEG data were recorded wide-band at 2 kHz. After video-EEG monitoring, brains were analyzed for thionine and Timm staining and glial fibrillary acid protein (GFAP) immunostaining. Key Findings: Unilateral injection of KA in dorsal hippocampus of guinea pigs induces an acute nonconvulsive status epilepticus (SE) that terminates within 24 h (n = 22). Chronic seizures with very mild motor signs (undetectable without EEG monitoring) and highly variable recurrence patterns appear in 45.5% (10 of 22) KAtreated animals, with variable delays from the initial SE. In these animals interictal events, CA1 cell loss, gliosis, and altered Timm staining pattern were observed. The induction of a chronic condition did not correlate with the duration of the nonconvulsive acute SE, but correlated with the extension and quality of neuropathologic damage. Significance: We demonstrate that a model of hippocampal (mesial temporal lobe) epilepsy can be developed in the guinea pig by intrahippocampal injection of KA. Seizure events in this model show little behavioral signs and may be overlooked without extensive video-EEG monitoring. The establishment of a chronic epileptic condition correlates with the extension of the hippocampal damage (mainly cell loss and gliosis) and not with the intensity of the initial SE.

Simultaneous enhancement of excitation and postburst inhibition at the end of focal seizures

“…Intracranial multichannel EEG signal analysis demonstrated that a parameter of synchronization (eigenvalue) is reduced during the early phases of a seizure and progressively augments when seizure end approaches. 5,32 These findings are consistent with the observation of irregular and asynchronous activity patterns during the early seconds of seizures recorded in vivo in animal models of epilepsy 14,[33][34][35] and during acute seizures on in vitro preparations. 8,10,36 Experimental studies performed on cortical and hippocampal slices maintained in vitro also suggest that seizures are initiated by a reduction of neuronal synchrony.…”

“…Brief applications of either the c-aminobutyric acid (GABA) A receptor blocker, bicuculline methiodide (BMI), or the potassium channel blocker, 4-aminopyridine (4AP), induced in the hippocampus and in the parahippocampal region a typical focal seizure pattern that initiates with low-voltage fast activity, followed by irregular spiking activity; the late phase of the ictal discharge is characterized by large-amplitude, synchronous bursts that recur periodically [6][7][8][9][10] and show widespread propagation. 11 A similar sequence of events was observed during seizures recorded in the limbic cortex of animal models of temporal lobe epilepsy developed in rats, 12 mice, 13 and guinea pigs 14 and in human seizures recorded with intracerebral electrodes during presurgical monitoring studies in patients with pharmacoresistant focal epilepsies. [15][16][17][18][19] We explore here the possibility that enhancement of excitation during the late periodic ictal bursting induces a progressive enhancement of inhibition (depression) that brings seizures to end.…”

“…7,8,14 Typical seizure patterns are illustrated in Figures 2A and 3A. Seizure onset featured fast, low-voltage activity in the beta/ gamma range followed by irregular spiking.…”

The vulnerability of calretinin-containing hippocampal interneurons to temporal lobe epilepsy

“…These models usually show remarkable similarity to human hippocampal pathology in TLE (Sloviter, 1996; Bernard et al, 1998; Ben-Ari, 2001; Sharma et al, 2007; Curia et al, 2008; Tang and Loke, 2010; Carriero et al, 2012), including sclerosis, loss of pyramidal cells in the CA1 and CA3c regions, hilar interneuronal loss, and the preservation of calbindin-containing interneurons (Sloviter et al, 1991; Wittner et al, 2002). …”

The in vitro isolated whole guinea pig brain as a model to study epileptiform activity patterns

“…Advantages and disadvantages of the in vitro IWB in comparison to other in vitro models and to the in vivo condition are summarized in Table 1. As future advancement, we plan to isolate brains from chronically epileptic guinea pigs (Arcieri et al, 2014;Carriero et al, 2012) to study network changes induced by the epileptogenic process.…”