Abstract
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 (PrPC) in REST-dependent homeostasis and the developmental switch of NMDARs. REST and REST-associated proteins were overactivated in the hippocampi of Prnp knockout mice (Prnp0/0) compared with wild-type Prnp (Prnp+/+) mice. This coincided with the disruption of the normal developmental switch from GluN2B-to-GluN2A in vivo. PrPC 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 PrPC not only disrupted REST-mediated distribution of mitochondria, but also prevented REST-regulated expression of GluN2B and GluN2A in Prnp0/0. Importantly, these effects were rescued after overexpression of full-length PrPC through restoration of NMDAR2 subunits and their distributions in dendritic processes in Prnp0/0. Consistently, knockdown of PrPC in Prnp+/+ had a similar effect on Prnp0/0. Furthermore, PrPC colocalized with both GluN2B and GluN2A in Prnp+/+. For the first time, we demonstrate that PrPC 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.
Highlights
N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels critical for synaptogenesisNR2 (GluN2) is a key determinant of the functional capabilities of NMDARs, including activation, deactivation and desensitization kinetics[4]
Comparing wild-type (WT; Prnp+/+) and Prnp knockout (Prnp0/0) mice primary cultured hippocampal neurons, we found that PrPC affects the translocation of repressor element 1-silencing transcription factor (REST), and partially mediates REST-regulated mitochondria distribution and the developmental switch in synaptic NMDARs
In the WT group, contrary to the tendency of PrPC, a transient, but marked increase in REST abundance occurred at postnatal day 3 (P3; Fig. 1a, b), with a subsequent, and constant, abundance of GluN2B protein from P7 until P13
Summary
N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels critical for synaptogenesisNR2 (GluN2) is a key determinant of the functional capabilities of NMDARs, including activation, deactivation and desensitization kinetics[4]. N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels critical for synaptogenesis. A developmental switch from containing primarily GluN2B-to-GluN2A occurs during postnatal development in NMDARs5. This switch, as well as the correct GluN2A/CluN2B ratio, is critical for Official journal of the Cell Death Differentiation Association. Song et al Cell Death and Disease (2018)9:541 neural circuitry[6], hippocampus-dependent learning[7], plasticity-induced alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors[8] and spine growth[9]. A previous report has shown that the transcriptional repressor element 1-silencing transcription factor (REST), known as neuron-restrictive silencer factor[10], participates in the postnatal switch in synaptic. REST shows both target and temporal characteristics in differentiated neurons for GluN2B11. As a switch from primarily GluN2B-to-GluN2A, the mechanisms that trigger
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