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Individuals with schizophrenia can experience auditory hallucinations and delusions, as well as disrupted cognitive and sensory processes that may result in functional impairment and long-term disability. In the cerebral cortex, pyramidal cells are essential to the cognitive and sensory processes that may be disrupted in schizophrenia.

Postmortem studies of individuals with schizophrenia consistently show deficits in dendritic architecture in layer 3 pyramidal cells in multiple brain regions, including the auditory cortex.

To improve our understanding of the neurobiological basis of these dendritic architectural impairments, investigators including Melanie Grubisha, MD, PhD (Assistant Professor of Psychiatry), Shinnyi (Cindy) Chou, MD, PhD (PGY5 Child and Adolescent Psychiatry Fellow), and Robert Sweet, MD (UPMC Endowed Professor in Psychiatric Neuroscience and Professor of Neurology and Clinical and Translational Science), from Pitt Psychiatry studied layer 3 pyramidal neurons, dendrites, and dendritic spines in a mouse model harboring a mutation in a gene (Kalrn) known to regulate dendritic development. 

“Dendrites grow rapidly prior to adolescence, but then exhibit stability throughout adolescence and adulthood. We hypothesized that this stability is dynamic, resultant from balanced opposition of growth and retraction pathways. We nominated an important yet understudied pathway, OMGp/NGR1/KAL9, as an important regulator of dendritic regression. We hypothesized that this pathway typically increases in activity during adolescence and adulthood to counterbalance the growth signals, and that a gain-of-function in its signaling could lead to an imbalance and net dendritic regression,” said Dr. Grubisha, first author of the study, which was recently published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).

The team found that dendrites retain the capacity for growth and that a mild genetic enhancement of the OMGp/NGR1/KAL9 pathway leads to the onset of structural impairments in previously formed dendrites across adolescence. 

“Dr. Grubisha’s findings have identified a new mechanism by which increased levels of OMGp, a normally occurring adolescent developmental process, can lead to completely normal development prior to adolescence, only to veer into pathology during adolescence, all due to a minor genetic alteration,” said Dr. Sweet, the study’s senior author. “This pathway may thus underlie the vulnerability to many different psychiatric disorders that display just that pattern: healthy childhood development, followed by deterioration in adolescence or early adulthood.” 
 
A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development
Grubisha MJ, Sun T, Eisenman L, Erickson SL, Chou S, Helmer CD, Trudgen MT, Ding Y, Homanics GE, Penzes P, Wills ZP, Sweet RA
PNAS December 7, 2021 118 (49) e2022546118; https://doi.org/10.1073/pnas.2022546118