A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

Abstract

Many animal prototypes illustrating the various attributes of human temporal lobe epilepsy (TLE) are available. These models have been invaluable for comprehending multiple epileptogenic processes, modifications in electrophysiological properties, neuronal hyperexcitability, neurodegeneration, neural plasticity, and chronic neuroinflammation in TLE. Some models have also uncovered the efficacy of new antiepileptic drugs or biologics for alleviating epileptogenesis, cognitive impairments, or spontaneous recurrent seizures (SRS). Nonetheless, the suitability of these models for testing candidate therapeutics in conditions such as chronic TLE is debatable because of a lower frequency of SRS and an inconsistent pattern of SRS activity over days, weeks or months. An ideal prototype of chronic TLE for investigating novel therapeutics would need to display a large number of SRS with a dependable frequency and severity and related co-morbidities. This study presents a new kainic acid (KA) model of chronic TLE generated through induction of status epilepticus (SE) in 6-8 weeks old male F344 rats. A rigorous characterization in the chronic epilepsy period validated that the animal prototype mimicked the most salient features of robust chronic TLE. Animals displayed a constant frequency and intensity of SRS across weeks and months in the 5th and 6th month after SE, as well as cognitive and mood impairments. Moreover, SRS frequency displayed a rhythmic pattern with 24-hour periodicity and a consistently higher number of SRS in the daylight period. Besides, the model showed many neuropathological features of chronic TLE, which include a partial loss of inhibitory interneurons, reduced neurogenesis with persistent aberrant migration of newly born neurons, chronic neuroinflammation typified by hypertrophied astrocytes and rod-shaped microglia, and a significant aberrant mossy fiber sprouting in the hippocampus. This consistent chronic seizure model is ideal for investigating the efficacy of various antiepileptic drugs and biologics as well as understanding multiple pathophysiological mechanisms underlying chronic epilepsy.

Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain

“…Briefly, the isolation and expansion of human bone marrow-derived MSCs in culture, isolation, and characterization of EVs were done as described in our previous reports [20,24]. Induction of SE in rats was performed using procedures detailed in previous reports [28][29][30]. IN administration of 10 billion EVs was performed 2.5 h after the induction of SE following permeabilization of the nasal mucous membrane with hyaluronidase for 30 min (Figure 1).…”

“…After a week of acclimatization in the vivarium, SE was induced in the rats via graded hourly intraperitoneal injections of kainic acid (KA, 5 mg/Kg) for 2-5 h until they displayed either a state of continuous stage 4 seizures characterized by bilateral forelimb clonus with signs of rearing, or a first stage 5 seizure typified by bilateral forelimb clonus with rearing and falling followed by continuous stages 3-5 seizures for over 10 min [28][29][30]42,44]. Rats continuously displayed stages of III-V seizures for two hours after the onset of SE.…”

Neural Activities in Multiple Rat Brain Regions in Lithium-Pilocarpine-Induced Status Epilepticus Model

“…Status epilepticus (SE) is one of the most severe conditions of epilepsy, which is caused by a hypersynchronous activation of neurons. If SE is untreated, it could result in severe brain damage or death (Hellier and Dudek, 1999;Trinka et al, 2012;Leitinger et al, 2019;Upadhya et al, 2019). In the lithium-pilocarpine model, pilocarpine, which is a directacting cholinergic muscarinic agonist, is administered after pretreatment with lithium to induce continuous seizures; this model is a popular model of acute SE and chronic TLE, which develops within days to weeks after experimental SE (Lévesque et al, 2016).…”

The Paradox of Astroglial Ca2 + Signals at the Interface of Excitation and Inhibition

“…Astrocyte (dys-) functions have been causally linked to the etiology of TLE (Bedner et al, 2015;Steinhäuser et al, 2016;Deshpande et al, 2020). On a cellular and molecular level, this is paralleled by a selective vulnerability of GABAergic interneurons (Sanon et al, 2005;Upadhya et al, 2019) and reduced glutamate decarboxylase (GAD) as well as glutamine synthetase (GS) activity in astrocytes (Robel and Sontheimer, 2016;Chan et al, 2019), leading to reduced vesicular GABA levels in neurons and subsequently reduced inhibitory input on hippocampal pyramidal neurons (Liang et al, 2006). However, glutamate levels also increase (Luna-Munguia et al, 2011) and a re-emergence of astroglial mGluR5 receptors can be observed (Umpierre et al, 2019).…”