A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development
Melanie Grubisha, Tao Sun, Leanna Eisenman, Susan Erickson, Shinnyi Chou, Cassandra Helmer, Melody T. Trudgen, Ying Ding, Gregg E. Homanics, Peter Penzes, Zachary P. Wills, Robert A. Sweet
Abstract
, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wild-type KAL. In mice containing this missense mutation at the endogenous locus, there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Spine density per unit length of dendrite is unaffected. Early adult mice with these structural deficits exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease.