Mice hemizygous for this DISC1-cc transgene are viable and fertile, with expression of a tamoxifen-inducible, LBDG521R-DISC1-cc fusion protein directed to the branches of cortex, hippocampus, striatum, and cerebellum neurons (cytoplasm) of the forebrain by the mouse CaMKIIα promoter. The fusion protein consists of a truncated mutant isoform of the mouse disrupted-in-schizophrenia-1 gene (DISC1-cc; containing only residues (671-852) critical for NUDEL and Lis1 binding) and a mutant form of the human estrogen receptor ligand binding domain (LBDG521R; which is unable to bind its natural ligand, estrogen, at physiological concentrations but will bind the synthetic ligand, 4-hydroxytamoxifen). Prior to tamoxifen administration, the fusion protein is sequestered by chaperone proteins and is degraded. Upon tamoxifen binding, the fusion protein is released from the chaperone proteins and is then free to compete/interfere with endogenous Disc1 binding, thus having a dominant-negative function. Early postnatal, but not adult, tamoxifen-induced expression of the fusion protein results in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, depressive-like traits, abnormal spatial working memory, and reduced sociability. Of note, the homozygous phenotype is not yet characterized (July 2012) as the donating investigator has not attempted to breed hemizygous mice together to make homozygous mice.
