Synaptic Activity Controls Nuclear ERK/CREB Signaling Via Appll-mediated Retrograde Dendritic Translocation Of TrkB Endosomes

Activity-dependent modification of gene expression(excitation-transcription coupling)is a powerful means by which the neurons build up stable changes of neuronal properties,a process that is essential for long-term synaptic plasticity and memory.Synaptic information encoded in calcium waves or in protein messengers is conveyed from synapse to the nucleus to elicit transcriptional responses.CREB(Ca2+/cAMP-responsive element binding protein)is a key transcription regulator that can be activated by phosphorylation in response to external stimuli and is critical for CRE-mediated gene expression and many adaptive changes in neurons.Despite many studies,basic questions remain about mechanisms for synapse-to-nucleus communication along the dendrites.TrkB belongs to the large RTK(Receptor tyrosine kinase)family and is a high affinity receptor for the neurotrophin BDNF(Brain derived neurotrophic factor).BDNF binding to TrkB triggers autophosphorylation of tyrosine residue in its intracellular domain and internalization into early endosomes.Upon HFS(High-frequency stimulation)or TBS(Theta-burst stimulation),BDNF is secreted in response to Ca2+ influx through NMDA receptor or voltage-gated Ca2+channels.Genetic deletion of bdnf or its receptor TrkB,or treatment with BDNF-specific antibodies or TrkB-IgG impairs L-LTP.Exogenously applied BDNF induces LTP in the medial perforant path input to dentate gyrus,which is suppressed by the transcription inhibitor Actinomycin D.BDNF has been shown to induce expression of proteins that potentially regulate synapse function,such as activity-regulated cytoskeletal protein.These findings support a critical role of BDNF/TrkB signaling during transcription-dependent phase of neuronal plasticity.However,little is known about the mechanism underlying retrograde delivery of BDNF/TrkB signaling from the activated synapses to the nucleus.APPL1(Adaptor protein containing pH domain,PTB domain,and leucine zipper motif)is a marker of early endosomes and also signaling endosome.Previous studied that APPL1 couples NMDA(N-methyl-D-aspartate)receptor with neuronal pro-survival PI3K(Phosphatidylinositol 3-Kinase)/AKT pathway.In this study,we identify a signaling pathway characterized by APPL1-mediated TrkB retrograde dendritic trafficking for long-distance communication between synapse and nucleus.We firstly demonstrate that TrkB endosomes induced by synaptic activity bear endocytic adaptor APPL1.Further analysis reveals that APPL1 contains a nuclear localization signal and mediates retrograde dendritic transport of TrkB via direct binding of APPL1 to Importin al.Disrupting APPL1-Importin al interaction by interfering peptide abolishes this retrograde trafficking of TrkB.Additionally,disrupting either APPLl-Importin al or APPL1-TrkB interaction blocks nuclear import of phosphor-ERK.Interrupting this pathway also impairs the sustained CREB phosphorylation triggered by synaptic activity,the maintenance of hippocampal late-phase LTP and long-term memory in mice.Thus,APPL1-mediated TrkB retrograde dendritic transport is essential for long-term synaptic plasticity and memory via coupling of neuronal activity with the maintenance of nuclear ERK/CREB activation.