Carboxypeptidase E conditional knockout mice exhibit learning and memory deficits and neurodegeneration

Carboxypeptidase E (CPE) is a multifunctional protein with many nonenzymatic functions in various systems. Previous studies using CPE knock-out mice have shown that CPE has neuroprotective effects against stress and is involved in learning and memory. However, the functions of CPE in neurons are still largely unknown. Here we used a Camk2a-Cre system to conditionally knockout CPE in neurons. The wild-type, CPE(flox/−), and CPE(flox/flox) mice were weaned, ear-tagged, and tail clipped for genotyping at 3 weeks old, and they underwent open field, object recognition, Y-maze, and fear conditioning tests at 8 weeks old. The CPE(flox/flox) mice had normal body weight and glucose metabolism. The behavioral tests showed that CPE(flox/flox) mice had impaired learning and memory compared with wild-type and CPE(flox/-) mice. Surprisingly, the subiculum (Sub) region of CPE(flox/flox) mice was completely degenerated, unlike the CPE full knockout mice, which exhibit CA3 region neurodegeneration. In addition, doublecortin immunostaining suggested that neurogenesis in the dentate gyrus of the hippocampus was significantly reduced in CPE(flox/flox) mice. Interestingly, TrkB phosphorylation in the hippocampus was downregulated in CPE(flox/flox) mice, but brain-derived neurotrophic factor levels were not. In both the hippocampus and dorsal medial prefrontal cortex, we observed reduced MAP2 and GFAP expression in CPE(flox/flox) mice. Taken together, the results of this study demonstrate that specific neuronal CPE knockout leads to central nervous system dysfunction in mice, including learning and memory deficits, hippocampal Sub degeneration and impaired neurogenesis.