A Critical Role For Exicitation-transcription Of Autophagy Genes Regulated By CRTC1-CREB In Endocytosis Of Synaptic AMPA Receptors

Background The cAMP-response element binding protein(CREB)and its CREB-regulated transcription coactivator 1(CRTC1)are widely expressed in the brain,both of which are transcription factors that can activate the transcription of related genes in response to neuronal activity.They play an important role in the maintenance of transcription-dependent synaptic plasticity.Studies have found that LTP(long-term potentiation)could induce the nucleus translocation of CRTC1,which leads to the transcription of early genes such as c-fos,Arc and BDNF and mediates the maintenance of LTP.In addition,CREB also plays an important role in maintaining long-term inhibition(LTD),while the roles of CRTC1 in LTD are unclear.CRTC2,a direct homologous gene of CRTC1,can mediate the transcription of autophagy-related genes in mouse liver cells.Bioinformatics analysis suggests that the functions of CRTC1 are similar to CRTC2,so CRTC1 may mediate the transcription of autophagy-related genes in neurons.The degradation of synaptic proteins and AMPA receptors is critical for the maintenance of LTD in neurons.Therefore,we wanted to investegate whether CRTC1 could translocate into the nucleus under cLTD and mediate the transcription of autophagy-related genes to degrade AMPA receptors.Objectives To detect whether CRTC1 can translocate into the nucleus under cLTD to trigger the expression of autophagy-related genes and participate in the endocytic degradation of AMPA receptors.Methods Using q PCR,immustaining,CHIP and western blot to investigate whether cLTD induce the transcription of autophagy-related genes mediated by CRTC1 and promote the the neuronal autophagy level.Performing immunostaining to detect the effects of CRTC1 and autophagy on GluR1 endocytosis induced by cLTD.Results Under the stimulation of cLTD,CRTC1 translocated into the nucleus and combined with CREB to the promoter of autophagy-related genes to activate gene transcription,which promoted the neuronal autophagy level and degraded endocytic synapse related proteins and GluR1.