A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 49; pp. 1 - 12
• Main Authors: Grubisha, Melanie J., Sun, Tao, Eisenman, Leanna, Erickson, Susan L., Chou, Shinny-yi, Helmer, Cassandra D., Trudgen, Melody T., Ding, Ying, Homanics, Gregg E., Penzes, Peter, Wills, Zachary P., Sweet, Robert A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.12.2021
• Subjects: Adolescents; Animals; Autopsy; Biological Sciences; Cerebral cortex; Cerebral Cortex - cytology; Child development; Complexity; Cortex (auditory); CRISPR-Cas Systems; Dendrites; Dendrites - physiology; Dendritic spines; Dendritic structure; Density; Gene Expression Regulation, Developmental - physiology; Genetic code; Genotype; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Guanine; Guanine nucleotide exchange factor; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Heterogeneity; Humans; Mental disorders; Mice; Mice, Transgenic; Missense mutation; Mutation; Mutation, Missense; Myelin Proteins - genetics; Myelin Proteins - metabolism; Neurons - physiology; Nogo protein; Nogo Receptor 1 - genetics; Nogo Receptor 1 - metabolism; Nucleotides; Phenotypes; Pyramidal cells; RhoA protein; Schizophrenia; Sexual Maturation; Signal Transduction - physiology; Signs and symptoms; Spine; Substantia grisea; Kalirin; adolescence; dendrite; NGR1
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2022546118

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.