Carboxypeptidase E Regulates Activity-Dependent TrkB Neuronal Surface Insertion and Hippocampal Memory

Activity-dependent insertion of the tropomyosin-related kinase B (TrkB) receptor into the plasma membrane can explain, in part, the preferential effect of brain-derived neurotrophic factor (BDNF) on active neurons and synapses; however, the under-lying molecular mechanisms remain obscure. Here, we report a novel function for carboxypeptidase E (CPE) in controlling chemical long-term potentiation stimuli-induced TrkB surface delivery in hippocampal neurons. Total internal reflection fluo-rescence assays and line plot assays showed that CPE facilitates TrkB transport from dendritic shafts to the plasma mem-brane. The Box2 domain in the juxtamembrane region of TrkB and the C terminus of CPE are critical for the activity-dependent plasma membrane insertion of TrkB. Moreover, the transactivator of transcription TAT-CPE452-466, which could block the association between CPE and TrkB, significantly inhibited neuronal activity-enhanced BDNF signaling and dendritic spine morphologic plasticity in cultured hippocampal neurons. Microinfusion of TAT-CPE452-466 into the dorsal hippocampus of male C57BL/6 mice inhibited the endogenous interaction between TrkB and CPE and diminished fear-conditioning-induced TrkB phosphorylation, which might lead to an impairment in hippocampal memory acquisition and consolidation but not re-trieval. These results suggest that CPE modulates activity-induced TrkB surface insertion and hippocampal-dependent mem-ory and sheds light on our understanding of the role of CPE in TrkB-dependent synaptic plasticity and memory modulation.

Automated summary

The study reveals a crucial role of CPE in controlling the surface delivery of TrkB receptor, which in turn impacts the activity of neurons and synapses. This finding may contribute to a better understanding of the role of CPE in TrkB-dependent synaptic plasticity and memory modulation.