title: Carbamazepine Prevents Hippocampal Neurodegeneration in Mice Lacking the Neuroprotective Protein, Carboxypetidase E.
abstract: Carboxypeptidase E (CPE) has recently been described as a neuroprotective protein, and in mice devoid of CPE, a complete loss of the hippocampal CA3 neurons is observed. The pattern of loss is characteristic of that caused by status epilepticus. We therefore set out to determine when this loss occurred, what might induce it and if it could be prevented. We found that the hippocampus was intact in 4 week old CPE knock out (KO) mice that had not undergone weaning. However, weaning of 2 or 3 week old CPE KO mice, which involves maternal separation (emotional stress) and ear tagging and tail snipping for genotyping (physical stress), resulted in degeneration of the CA3 neurons by 3 and 4 weeks of age, respectively, while the wild-type mice were unaffected. Moreover, the physical stress caused a more severe neurodegeneration phenotype than the emotional stress of the maternal separation alone. Daily treatment with carbamazepine, an antiepileptic agent, in 2 week old CPE KO mice for 2 weeks prevented the neurodegeneration, despite the weaning process at 3 weeks. No further neurodegeneration was observed 3 weeks post weaning in carbamazepine treated mice. These results showed that degeneration of the CA3 neurons in the hippocampus, previously observed in 6 week old CPE KO mice, is not due to a developmental defect, but caused by physical and emotional stress during the weaning process. This degeneration was prevented by carbamazepine suggesting that the stress associated with weaning caused epileptic-like events in the CPE KO mice.
authors.affiliation: Section on Cellular Neurobiology, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute on Child Health and Human Development, National Institutes of Health, USA.
authors.forename: Alicja
authors.initials: A
authors.lastname: Woronowicz
authors.affiliation: Section on Cellular Neurobiology, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute on Child Health and Human Development, National Institutes of Health, USA.
authors.forename: Niamh X
authors.initials: NX
authors.lastname: Cawley
authors.affiliation: Section on Cellular Neurobiology, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute on Child Health and Human Development, National Institutes of Health, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Peng Loh
keywords: Epilepsy; Maternal separation; Neurodegeneration; Stress; Weaning