Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-12, Vol.108 (49), p.E1349-E1358
• Main Authors: Kvajo, Mirna, McKellar, Heather, Drew, Liam J, Lepagnol-Bestel, Aude-Marie, Xiao, Lan, Levy, Rebecca J, Blazeski, Richard, Arguello, P. Alexander, Lacefield, Clay O, Mason, Carol A, Simonneau, Michel, O'Donnell, James M, MacDermott, Amy B, Karayiorgou, Maria, Gogos, Joseph A
• Format: Article
• Language: English
• Subjects: Action Potentials; adults; Animal models; Animals; Animals, Newborn; Axon guidance; Axons - metabolism; Biological Sciences; Brain; Cell Proliferation; Cells, Cultured; Circuits; Cyclic AMP; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Dendrites - metabolism; Dendrites - physiology; Dentate gyrus; Dentate Gyrus - cytology; Dentate Gyrus - growth & development; Dentate Gyrus - metabolism; DISC1 protein; Hippocampus; Hippocampus - cytology; Hippocampus - growth & development; Hippocampus - metabolism; Immunohistochemistry; Long-Term Potentiation; Mental disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; mossy fibers; Mossy Fibers, Hippocampal - metabolism; mutants; Mutation; Neonates; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural networks; Neurogenesis; Neuronal Plasticity; Neurons - cytology; Neurons - metabolism; Neurons - physiology; Patch-Clamp Techniques; pathogenesis; Plasticity (axonal); PNAS Plus; Risk factors; Rodents; Schizophrenia
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1114113108

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.