Carboxypeptidase E knockout mice exhibit abnormal dendritic arborization and spine morphology in central nervous system neurons

Abstract

Carboxypeptidase E (CPE) is involved in maturation of neuropeptides and sorting of brain-derived neurotrophic factor (BDNF) to the regulated pathway for activity-dependent secretion from CNS neurons. CPE knock-out (CPE-KO) mice have many neurological deficits including learning and memory. Here, we analyzed the dendritic arborization and spine morphology of CPE-KO mice to determine a possible correlation of defects in such structures with the neurological deficits observed in these animals. Analysis of pyramidal neurons in layer V of cerebral cortex and in hippocampal CA1 region in 14 week old CPE-KO mice showed more dendritic complexity compared to wild type (WT) mice. There were more dendritic intersections and more branch points in CPE-KO versus WT neurons. Comparison of pyramidal cortical neurons in 6 week versus 14 week old WT mice showed a decrease in dendritic arborization, reflecting the occurrence of normal dendritic pruning. However, this did not occur in CPE-KO neurons. Furthermore, analysis of spine morphology demonstrated a significant increase in the number of D-type spines regarded as non-functional in the cortical neurons of CPE-KO animals. Our findings suggest that CPE is an important novel player in mediating appropriate dendritic patterning and spine formation in CNS neurons.

Carboxypeptidase E (NF-α1): a new trophic factor in neuroprotection

“…In contrast to the increased CPE, the offspring of pregnant ewes subjected to aversive interactions with human handlers show a decrease in CPE concomitant with abnormal dendritic spine density and morphogenesis in the prefrontal cortex and hippocampus [14] . This is consistent with a report showing that CPE KO mice exhibit abnormal dendritic arborization and spine morphology in these areas [15] , demonstrating that CPE plays a role in normal cytoarchitecture and neuronal function in these brain regions. Supporting evidence came from the finding that CPE is a binding partner for nitric oxide synthase 1 adaptor protein, a protein involved in the regulation of dendritic patterning in hippocampal neurons [16] .…”

The Molecular Profiles of Neural Stem Cell Niche in the Adult Subventricular Zone

“…However, an N-terminal truncated isoform of CPE (CPE-ΔN) was found to drive tumor progression in different types of cancer [88]. In the nervous system, CPE exerts its function in neuroprotection [89] and dendrite development [90], [91]. Our experiment showed that in the presence of recombinant CPE, fewer neurospheres were formed (p<0.0001) and the average neurosphere diameter was significantly smaller than the control (p = 0.031).…”

Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density

“…We initially characterized the CPE KO mouse with respect to its most obvious phenotypes: obesity, diabetes, and infertility (7). Other studies on CPE KO mice have shown defective secretion of mature brain-derived neurotrophic factor (BDNF) in the hippocampus (26), defective secretion of glutamate in the retina (40), specific neuronal degeneration in the CA3 region of the hippocampus (36), and defective dendritic pruning and spine formation of layer V cortical neurons (6,35). Thus CPE appears to play a role, either directly or indirectly, in many processes both inside and outside the central nervous system.…”