REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors

Expression of GluN2 subunit of NMDA receptor (NMDAR) in rodents is developmentally regulated such that GluN2B expression is high during early postnatal period but is replaced by GluN2A in adulthood, thus conferring different NMDAR channel properties and kinetics. This study identifies a molecular mechanism for GluN2A/B switch that is mediated by the transcriptional repressor REST. This process is also shown to be affected by postnatal stress induced by maternal deprivation, leading to long-lasting effects on NMDAR-subunit composition in the hippocampus. NMDA receptors (NMDARs) are critical to synaptogenesis, neural circuitry and higher cognitive functions. A hallmark feature of NMDARs is an early postnatal developmental switch from those containing primarily GluN2B to primarily GluN2A subunits. Although the switch in phenotype has been an area of intense interest for two decades, the mechanisms that trigger it and the link between experience and the switch are unclear. Here we show a new role for the transcriptional repressor REST in the developmental switch of synaptic NMDARs. REST is activated at a critical window of time and acts via epigenetic remodeling to repress Grin2b expression and alter NMDAR properties at rat hippocampal synapses. Knockdown of REST in vivo prevented the decline in GluN2B and developmental switch in NMDARs. Maternal deprivation impaired REST activation and acquisition of the mature NMDAR phenotype. Thus, REST is essential for experience-dependent fine-tuning of genes involved in synaptic plasticity.