Prion protein is essential for the RE1 silencing transcription factor (REST)-dependent developmental switch in...

It is important that the correct amounts of GluN2 subunits are maintained, as they determine NMDAR functional properties, which are crucial to neuronal communication, synaptogenesis and cognitive function. The transcriptional repressor RE1 silencing transcription factor (REST) is critical for the postnatal developmental switch in NMDARs. However, the mechanisms triggering REST and the link between NMDARs and REST are unclear. Here we show a new physiological essential role for cellular prion protein (PrP^C) in REST-dependent homeostasis and the developmental switch of NMDARs. REST and REST-associated proteins were overactivated in the hippocampi of Prnp knockout mice (Prnp ^0/0 ) compared with wild-type Prnp (Prnp ^+/+ ) mice. This coincided with the disruption of the normal developmental switch from GluN2B-to-GluN2A in vivo. PrP^C co-located with REST under physiological environments and mediated the translocation of REST in conditioners of NMDARs in vitro in Prnp ^+/+ hippocampal neurons. Regardless of whether REST was knocked down or overexpressed, deletion of PrP^C not only disrupted REST-mediated distribution of mitochondria, but also prevented REST-regulated expression of GluN2B and GluN2A in Prnp ^0/0 . Importantly, these effects were rescued after overexpression of full-length PrP^C through restoration of NMDAR2 subunits and their distributions in dendritic processes in Prnp ^0/0 . Consistently, knockdown of PrP^C in Prnp ^+/+ had a similar effect on Prnp ^0/0 . Furthermore, PrP^C colocalized with both GluN2B and GluN2A in Prnp ^+/+ . For the first time, we demonstrate that PrP^C is essential for REST-regulated NMDARs. Confirming the regulation of NMDAR-modulating mechanisms could provide novel therapeutic targets against dysfunctions of glutamatergic transmission in the nervous system.