1. Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice.
- Author
-
Kvajo M, McKellar H, Drew LJ, Lepagnol-Bestel AM, Xiao L, Levy RJ, Blazeski R, Arguello PA, Lacefield CO, Mason CA, Simonneau M, O'Donnell JM, MacDermott AB, Karayiorgou M, and Gogos JA
- Subjects
- Action Potentials, Animals, Animals, Newborn, Cell Proliferation, Cells, Cultured, Cyclic AMP metabolism, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Dendrites metabolism, Dendrites physiology, Dentate Gyrus cytology, Dentate Gyrus growth & development, Dentate Gyrus metabolism, Hippocampus cytology, Hippocampus growth & development, Immunohistochemistry, Long-Term Potentiation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mossy Fibers, Hippocampal metabolism, Nerve Tissue Proteins genetics, Neurogenesis, Neurons cytology, Neurons metabolism, Neurons physiology, Patch-Clamp Techniques, Axons metabolism, Hippocampus metabolism, Nerve Tissue Proteins metabolism, Neuronal Plasticity
- Abstract
Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.
- Published
- 2011
- Full Text
- View/download PDF