The functions of repressor element 1-silencing transcription factor in models of epileptogenesis and post-ischemia

Abstract

Epilepsy is a debilitating neurological disorder characterised by recurrent seizures for which 30% of patients are refractory to current treatments. The genetic and molecular aetiologies behind epilepsy are under investigation with the goal of developing new epilepsy medications. The transcriptional repressor REST (Repressor Element 1-Silencing Transcription factor) is a focus of interest as it is consistently upregulated in epilepsy patients and following brain insult in animal models of epilepsy and ischemia. This review analyses data from different epilepsy models and discusses the contribution of REST to epileptogenesis. We propose that in healthy brains REST acts in a protective manner to homeostatically downregulate increases in excitability, to protect against seizure through downregulation of BDNF (Brain-Derived Neurotrophic Factor) and its receptor, TrkB (Tropomyosin receptor kinase B). However, in epilepsy patients and post-seizure, REST may increase to a larger degree, which allows downregulation of the glutamate receptor subunit GluR2. This leads to AMPA glutamate receptors lacking GluR2 subunits, which have increased permeability to Ca2+, causing excitotoxicity, cell death and seizure. This concept highlights therapeutic potential of REST modulation through gene therapy in epilepsy patients.

The homeostatic effects of the RE‐1 silencing transcription factor on cortical networks are altered under ictogenic conditions in the mouse

“…REST has been shown to play different roles under physiological conditions or under conditions of pathological hyperexcitability, ranging from homeostatic to pro‐epileptogenic effects 13,14,26,29,30 . However, a clear picture is still largely missing 29 .…”

“…11,12 3.5 | Deletion of Rest early in development attenuates the seizure severity in response to repeated administration of the convulsant pentylenetetrazole REST has been shown to play different roles under physiological conditions or under conditions of pathological hyperexcitability, ranging from homeostatic to pro-epileptogenic effects. 13,14,26,29,30 However, a clear picture is still largely missing. 29 To further elucidate the effects of the postnatal deletion of REST in neurons, we systemically administered the convulsant pentylenetetrazole (PTZ), known to alter network stability and homeostasis and simulate an epileptic-like condition by acting as a non-competitive antagonist of GABA A receptors.…”

“…13,14,26,29,30 However, a clear picture is still largely missing. 29 To further elucidate the effects of the postnatal deletion of REST in neurons, we systemically administered the convulsant pentylenetetrazole (PTZ), known to alter network stability and homeostasis and simulate an epileptic-like condition by acting as a non-competitive antagonist of GABA A receptors. 31,32 Rest GTi mice were injected at P0/P1 with the AAV vectors expressing ΔCre (PHP.eB hSyn1-NLS-GFP-ΔCre) or Cre (PHP.eB hSyn1-NLS-GFP-Cre) in neurons and were treated, 1 month later, with two injections of a threshold dose (60 mg/kg) of PTZ administered at a 48-h interval or with vehicle to allow for the occurrence of transcriptional responses triggered by the first critical event (Figure 6A).…”

Molecular Genetics of Acquired Temporal Lobe Epilepsy

“…Similar, REST/NRSF (repressor element 1 silencing transcription factor/neuron-restrictive silencer factor) is a regulator of channel expression and overexpressed in experimental models and humans with MTLE [ 119 , 120 ]. In a kindling model of TLE, resistant animals had higher protein levels of REST/NRSF, which may highlight a neuroprotective role against ictogenesis and hyperexcitability [ 121 , 122 ]. Furthermore, the downregulation of the BMAL1-PCDH19 (brain and muscle ARNT-Like 1, protocadherin 19) axis seems to be involved in the hyperexcitability of neurons following trauma and may explain daytime-dependent variations in seizure frequency [ 123 ].…”

Calcium Permeable-AMPA Receptors and Excitotoxicity in Neurological Disorders

“…regulatory element prevents the expression of neuronal genes important to synaptic plasticity including the AMPAR subunit GluA2 (Calderone et al, 2003;Noh et al, 2012;Butler-Ryan and Wood, 2021). Consisting of nine non-canonical zinc finger motifs, REST binds the cis-acting RE1 within the promoter region of the GluA2 gene (Chong et al, 1995;Schoenherr et al, 1996).…”