Pilocarpine-Induced Status Epilepticus Is Associated with Changes in the Actin-Modulating Protein Synaptopodin and Alterations in Long-Term Potentiation in the Mouse Hippocampus

Abstract

Epilepsy is a complex neurological disorder which can severely affect neuronal function. Some patients may experience status epilepticus, a life-threatening state of ongoing seizure activity associated with postictal cognitive dysfunction. However, the molecular mechanisms by which status epilepticus influences brain function beyond seizure activity remain not well understood. Here, we addressed the question of whether pilocarpine-induced status epilepticus affects synaptopodin (SP), an actin-binding protein, which regulates the ability of neurons to express synaptic plasticity. This makes SP an interesting marker for epilepsy-associated alterations in synaptic function. Indeed, single dose intraperitoneal pilocarpine injection (250 mg/kg) in three-month-old male C57BL/6J mice leads to a rapid reduction in hippocampal SP-cluster sizes and numbers (in CA1 stratum radiatum of the dorsal hippocampus; 90 min after injection). In line with this observation (and previous work using SP-deficient mice), a defect in the ability to induce long-term potentiation (LTP) of Schaffer collateral-CA1 synapses is observed. Based on these findings we propose that status epilepticus could exert its aftereffects on cognition at least in part by perturbing SP-dependent mechanisms of synaptic plasticity.

Complex modulation by stress of the effect of seizures on long term potentiation in mouse hippocampal slices

“…SE was induced by intraperitoneal (i.p.) injection of 250 mg/kg pilocarpine (Sigma Aldrich, pilocarpine hydrochloride), as previously described (Lenz, Ben Shimon, Deller, Vlachos, & Maggio, ). To avoid side effects induced by peripheral cholinergic activation, mice were pretreated with atropine methyl nitrate, a muscarinic acethylcholine receptor antagonist which does not cross the blood brain barrier (atropine, AMN, 1 mg/kg, i.p.…”

“…Control groups received the same treatment with atropine and diazepam, and were injected with saline instead of pilocarpine. After pilocarpine injection, behavioral seizure activity was assessed every 10 minutes by an investigator blind to the experimental conditions using the modified Racine's stages (Lenz et al, ). Mice were sacrificed either right after the drug exposure, at 12 hr, 24 hr, 1 week, 1 month, and 2 months after drug exposure.…”

A new model of experimental hemispherotomy in young adult Rattus norvegicus: a neural tract tracing and SPECT in vivo study

“…Experimental neurological approaches investigate the complex neurobiological mechanisms involved in epileptogenesis and the maintenance of seizures, 25 the development of new antiepileptic drugs, 9,18,20 alterations in synaptic plasticity, 26,50 the neurophysiological and neuropharmacological bases of the postictal immobility syndrome, 8,12 the characteristics of ictal and postictal states, 31 and postsurgical recovery skills. 5,40 None of these lines of research, however, are related to the resection of relevant cortical regions or disconnection of cortical tracts in animals undergoing acute and chronic models of generalized, multifocal, or limbic epileptic induction and cortical reorganization.…”

Desenvolvimento de um modelo experimental de hemisferotomia em ratos

“…No que diz respeito à neurologia experimental, ela investiga os complexos mecanismos neurobiológicos envolvidos na epileptogênese e manutenção de crises (Leite et al, 1990), desenvolvimento de novos fármacos antiepilépticos (Cunha et al, 2005;Fachim et al, 2011;Gelfuso et al, 2013), alterações na plasticidade sináptica (Vianna et al, 2005;Althaus et al, 2016;Willemse et al, 2016;Lenz et al, 2017), alterações neurofisiológicas e neurofarmacológicas na síndrome de imobilidade pós-ictal (Coimbra et al, 2001;de Oliveira et al, 2006;Cycowicz et al, 2008;Freitas et al, 2009;de Freitas et al, 2016), neurofisiologia do estado ictal e pós-ictal (Merricks et al, 2015) e recuperação pós-cirúrgica (Hertz-Pannier et al, 2002;Fournier et al, 2008;Save-Pedebos et al, 2016;Bulteau et al, 2017 Rasmussen (1983). B  Abordagem lateral proposta por Delalande (1992).…”