期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2022546118
关键词
dendrite; adolescence; NGR1; Kalirin
资金
- National Association for Research on Schizophrenia and Depression (NARSAD) Distinguished Investigator Grant from the Brain & Behavior Research Foundation Award
- NARSAD Young Investigator Award
- [MH118513-01]
- [MH071316]
- [MH097216]
- [AA020889]
- [R56AG058593]
- [MH071533]
The study demonstrates that the development of neuronal dendrites is regulated by the Nogo receptor 1 pathway, which is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor Kalirin-9. The research also shows that a missense mutation in the Kalrn gene identified in a schizophrenia cohort may lead to abnormal neuronal dendritic function, affecting the perception of gap durations in sound.
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.
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