Absence of Carboxypeptidase E/Neurotrophic Factor-Α1 in Knock-Out Mice Leads to Dysfunction of BDNF-TRKB Signaling in Hippocampus.

Carboxypeptidase E (CPE), first discovered as a prohormone processing enzyme, has also now been shown to be a secreted neurotrophic factor (neurotrophic factor-α1, NF-α1) that acts extracellularly as a signaling molecule to mediate neuroprotection, cortical stem cell differentiation, and antidepressive-like behavior in mice. Since brain-derived neurotrophic factor (BDNF) has very similar trophic functions, and its processing from pro-BDNF involves intracellular sorting of pro-BDNF to the regulated secretory pathway by CPE acting as a sorting receptor, we investigated whether the lack of CPE/NF-α1 would affect BDNF-TrkB signaling in mice. Previous studies have shown that CPE/NF-α1 knock-out (KO) mice exhibited severe neurodegeneration of the hippocampal CA3 region which raises the question of why other neurotrophic factors such as BDNF could not compensate for the deficiency of CPE. Here, we show that the expressions of pro-BDNF mRNA and protein in hippocampus of CPE-KO mice were similar to WT mice, but mature BDNF was ∼40% less in the CPE-KO mice, suggesting decreased intracellular processing of pro-BDNF. Furthermore, TrkB receptor levels were similar in both genotypes, but there was significantly decreased phosphorylation of TrkB receptor in the CPE-KO mice. Electrophysiological studies showed lack of formation of long-term potentiation in hippocampal slices of CPE-KO mice compared to WT mice, which was not rescued by application of BDNF, indicating dysfunction of the BDNF-TrkB signaling system. The CPE-KO mice showed normal postsynaptic AMPA response to kainate application in hippocampal slices and dissociated neurons. Our findings indicate that CPE/NF-α1 is essential for normal BDNF-TrkB signaling function in mouse hippocampus.