Phänotypische und molekulare Analyse einer Maus mit Insertionsmutation und axonaler Reorganisation im Hippocampus

Abstract

We generated a new epileptic mouse model showing massive late-onset aberrant mossy fiber sprouting in the adult hippocampus. The mutation of this mouse model derives from an intronic insertion of trangene DNA (TC) in the mouse phospholipase C-ß1 gene (PLC-ß1TC-/- -mutation) leading to a fully penetrant splice mutation and a complete loss of downstream PLC-ß1-expression. In detail, PLC-ß1TC-/- -mice exhibit a late-onset epileptiform hyperexcitability, behavioural modifications in a radial maze and an open field, juvenile retarded growth, enhanced postnatal mortality, a female nurturing defect and male infertility. Furthermore, PLC-ß1TC-/- -mutants develop a loss of NMDA-receptors in the stratum oriens of region CA1, apoptotic neuronal death, aberrant mossy- and calretinin- fiber sprouting and a reduced hippocampal PKC activity. Our studies provide evidence, that the arising of the behavioural phenotype in PLC-ß1TC-/--mice correlates in time with the development of the aberrant mossy fiber projections, indicating a functional role of axonal growth and reactive synaptogenesis in epileptogenesis. Kim and coworcers (1997) already reported coupling of PLC-ß1-mediated signal transduction to the muscarinic acetylcholine receptor pathway in both the cerebral cortex and hippocampus of a homologous recombinant PLC-ß1-/- -mouse model, but the adult sprouting-phenotype of PLC-ß1TC-/- -mice is now reported the first time. It is postulated, that the disruption of the PLC-ß1-mediated signal transduction pathway may lead to a functional cholinergic denervation of the hippocampus, which causes axonal remodelling in the adult hippocampus and leads in consequence to the observed epileptiform hyperexcitability.