Epub – Proceedings of the National Academy of Sciences of the United States
A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development

December 7, 2021

​Grubisha MJ, Sun T, Eisenman L, Erickson SL, Chou S, Helmer CD, Trudgen MT, Ding Y, Homanics GE, Penzes P, Wills ZP, Sweet RA

Normally, dendritic size is established prior to adolescence and then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, 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.

Grubisha MJ, Sun T, Eisenman L, Erickson SL, Chou S, Helmer CD, Trudgen MT, Ding Y, Homanics GE, Penzes P, Wills ZP, Sweet RA. A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development. PNAS December 7, 2021 118 (49) e2022546118; https://doi.org/10.1073/pnas.2022546118. PMCID: PMC8694055.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8694055/

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