Epigenetics in the adult brain: the role of REST in epilepsy

The Repressor Element 1 Silencing Transcription Factor (REST) is an epigenetic master regulator that plays a crucial role during the life of an individual. REST function was originally described in developmental stages, where it determines neuronal phenotype. However, recent studies showed that REST participates in several processes also in the adult brain, including neuronal plasticity and epileptogenesis. In this regard, the relationship between REST and epilepsy is still controversial and needs further investigation. Here, we studied the role of REST in epilepsy by inducing REST conditional knockout (REST-cKO) specifically in excitatory neurons in vivo. To target the excitatory neuronal population, we cloned the calcium/calmodulin-dependent protein kinase II (CaMKII) minimal promoter upstream of either the Cre recombinase or its inactive form. After assessing the specificity of the promoter’s expression, the aforementioned transgenes were packaged in an engineered adeno-associated virus (PHP.eB) able to cross the blood-brain and blood-cerebrospinal fluid barriers and delivered in the lateral ventricles of 2-month-old RESTflox/flox mice. We then characterized the cognitive phenotype (open field, novel object recognition, and social interaction tests) and the seizure propensity. We show that, with respect to control mice, REST-cKO mice display higher levels of anxiety and short-term memory deficits but have an unaltered social profile. Behavioral evaluation of the susceptibility to epileptic seizures shows that REST-cKO mice are more resistant to pentylenetetrazole (PTZ)-induced kindling, but not to seizures induced by a single PTZ shot, showing a higher survival rate. Overall, these data suggest that the absence of REST induces behavioral alterations and decreases seizure susceptibility. In addition, we developed and characterized genetic tools to specifically delete REST in other central nervous system (CNS) cellular populations (all neurons, inhibitory neurons, and glia) that will help us to draw a more precise and comprehensive picture of the role of REST in the physiopathology of the CNS.