Neuronal conditional knockout of <italic>NRSF</italic> decreases vulnerability to seizures induced by pentylenetetrazol in mice

Abstract

Neuron restrictive silencer factor (NRSF), also known as repressor element-1 silencing transcription factor, has been reported to modulate neuronal excitability and acts as endogenous anticonvulsant in kainic acid-induced or kindling-evoked seizure activity. However, whether NRSF functions in pentylenetetrazol (PTZ)-induced seizure activity has never been studied. To investigate the role of endogenous NRSF in the epileptogenesis induced by PTZ, in our experiment, NRSF neuronal conditional knockout mice (NRSF cKO) were adopted, in which NRSF was specifically deleted in neurons by the Cre-loxP system. Seizure threshold for PTZ, including the dose-response convulsions and the threshold dose, was compared between NRSF cKO and control mice. The threshold dose of PTZ that induced clonic and tonic seizures was significantly higher in NRSF cKO mice compared with the control. Similarly, the median lethal dose (LD 50 ) of PTZ in NRSF cKO mice was also considerably higher than that of the control mice. These results revealed that NRSF cKO mice are of higher resistance to convulsions induced by PTZ. Our work first demonstrated the function of NRSF in PTZ-induced seizure and provided new evidence for differential pathways in diverse types of seizure.

Effects of Intravenous Human Umbilical Cord Blood Mesenchymal Stem Cell Therapy versus Gabapentin in Pentylenetetrazole-Induced Chronic Epilepsy in Rats

“…In accordance with previous studies, the rats in this study were extremely susceptible to the development of kindling status by PTZ subconvulsant stimulation [33]. It is known that, by competitively interacting with GABA A receptors, PTZ induces convulsion in rats - presumably by impairing the GABA-mediated neuronal inhibition [34]. Additionally, competitive binding with GABA A receptor leads to an increase in calcium influx, causing mitochondrial disruption and the release of mediators responsible for the activation of the apoptotic cascade and cell death [35].…”

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

“…For example, UBE3A physically interacts with MECP2 33 (methyl CpG-binding protein 2, deleted in Rett syndrome) that represses a subset of genes through interactions with the NCoR repressor complex ( n uclear receptor co - r epressor) 34 . Seizures upregulate the transcriptional repressor REST ( RE -1 s ilencing t ranscription factor) in hippocampus 35,36 as well as in VTA (Extended Data Fig. 10f), and Cbln1 intron 2 contains a consensus RE-1 that binds REST 37 (Extended Data Fig.…”

Epigenetics and Epilepsy

“…Moreover, the assumption that NRSF-mediated gene repression promotes epileptogenesis was recently challenged by evidence that selective loss of NRSF from forebrain neurons accelerates kindling progression in mice (Hu et al 2011b). Mixed results were reported when REST was knocked out of all neurons, with no differences reported for clonic components at low doses in the PTZ model but protection against tonic components and death at higher doses (Liu et al 2012). Broad targeting of NRSF, therefore, may not be viable as a disease-modifying treatment in epilepsy.…”