Investigation Into The Function Of Transferrin Receptor1(TFR1)in The Purkinje Cells Of Mouse Cerebellum

Transferrin receptor 1(TFR1),a trans-membrane protein of clathrin complex,has an important role in cellular iron uptake.TFRI is abundantly expressed in the cerebellar cortex and deep cerebellar nuclei.It has been found that TFR1 is present in neuronal dendrites and co-localizes with pre/post-synaptic proteins.But the function of TFR1 in the CNS is unknown.To assess the roles of TFR1 in PCs,we generated conditional knockout mice(TFRlflox/flox;pCP2-cre)that specifically ablates TFR1 in PCs.We show that conditional knockout of TFR1 in PCs does not affect the cyto-architecture of PCs,but reduces mGlul expression at synapses.Group 1 metabotropic glutamate receptors(mGlul/5)are critical to synapse formation and participate in synaptic long-term potentiation(LTP)and long-term depression(LTD)in the brain.mGlul/5 signaling alterations have been documented in cognitive impairment,neurodegenerative disorders,and psychiatric diseases,but underlying mechanisms for its modulation are not clear.This regulation by TFR1 acts in concert with that by Rab8 and Rabll,which modulate the internalization and recycling of mGlul,respectively.TFR1 can bind to Rab proteins and facilitate their expression at synapses.In addition,PC ablation of TFR1 inhibits parallel fiber-PC LTD,whereas parallel fiber-LTP and PC intrinsic excitability are not affected.Increasing evidence has highlighted the importance of PC synaptic function for autism beyond classical motor-related behavior.we demonstrate that PC ablation of TFR1 impairs motor coordination but does not affect social behaviors in mice.Together,these findings underscore the importance of TFR1 in regulating mGlul trafficking and suggest that mGlul and mGlul-dependent parallel fiber-LTD are associated with regulation of motor coordination,but not autistic behaviors.