Disruption of PLC-β1-Mediated Signal Transduction in Mutant Mice Causes Age-Dependent Hippocampal Mossy Fiber Sprouting and Neurodegeneration

Abstract

Aberrant reorganization of hippocampal mossy fibers occurs in human temporal lobe epilepsy and rodent epilepsy models. We generated a mouse model showing massive late-onset aberrant mossy fiber sprouting in the adult hippocampus. The mutation in this mouse model derives from an intronic insertion of transgene DNA in the mouse PLC-β1 gene (PLC-β1 −/− TC mutation) leading to a splice mutation of the PLC-β1 gene and a complete loss of downstream PLC-β1 expression. PLC-β1 −/− TC mutants develop a loss of NMDA-receptors in the stratum oriens of region CA1, apoptotic neuronal death, and reduced hippocampal PKC activity. The phenotype of these mice further consists of a late-onset epileptiform hyperexcitability, behavioral modifications in a radial maze and in an open field, female nurturing defect, and male infertility. In the present study, we provide evidence that the arising of the behavioral phenotype in PLC-β1 −/− TC mice correlates in time with the development of the aberrant mossy fiber projections and that the disruption of the PLC-β1-mediated signal transduction pathway may lead to a functional cholinergic denervation, which could cause hippocampal remodeling and, in consequence, epileptiform hyperexcitability.