Abstract
Transferrin receptor (TFR) is an important iron transporter regulating iron homeostasis and has long been used as a marker for clathrin mediated endocytosis. However, little is known about its additional function other than iron transport in the development of central nervous system (CNS). Here we demonstrate that TFR functions as a regulator to control AMPA receptor trafficking efficiency and synaptic plasticity. The conditional knockout (KO) of TFR in neural progenitor cells causes mice to develop progressive epileptic seizure, and dramatically reduces basal synaptic transmission and long-term potentiation (LTP). We further demonstrate that TFR KO remarkably reduces the binding efficiency of GluR2 to AP2 and subsequently decreases AMPA receptor endocytosis and recycling. Thus, our study reveals that TFR functions as a novel regulator to control AMPA trafficking efficiency and synaptic plasticity.
Highlights
Transferrin receptor (TFR) is a trans-membrane glycoprotein for cellular iron uptake
We found that TFR expression was detected in mouse brain lysates as early as embryonic day 12.5 (E12.5), and reached the highest level between postnatal day 10 (P10) and P19 (Figure S1A)
TFR along with other synaptic proteins including GluR1, GluR2, postsynaptic density protein 95 (PSD95), synaptophysin and α -Ca2+/calmodulin-dependent protein kinase II (CamKII) all reached the highest expression level within the time window (P10 to P19) of brain outgrowth and synaptogenesis (Figure S1A), indicating that TFR may be associated with early brain development
Summary
Transferrin receptor (TFR) is a trans-membrane glycoprotein for cellular iron uptake. It binds to diferric transferrin and transports iron-transferrin complex at cell surface followed by clathrin-mediated endocytosis. The molecular and cellular mechanisms of TFR-dependent iron uptake and iron homeostasis pathway have been extensively studied in erythrocyte, liver, intestine and immune systems[1,2,3,4] and TFR has long been used as a clathrin mediated endocytic trafficking marker. TFR is expressed in several brain regions of mouse, enriched in endothelial cells[5], choroid plexus cells and neuron. Selective enrichment of TFR in brain regions, neuronal subpopulations and subcellular domains suggest that TFR participates in different physiological processes
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