TY - JOUR
T1 - Characterization hiPSC-derived neural progenitor cells and neurons to investigate the role of NOS1AP isoforms in human neuron dendritogenesis
AU - Crosta, Christen M.
AU - Hernandez, Kristina
AU - Bhattiprolu, Atul K.
AU - Fu, Allen Y.
AU - Moore, Jennifer C.
AU - Clarke, Stephen G.
AU - Dudzinski, Natasha R.
AU - Brzustowicz, Linda M.
AU - Paradiso, Kenneth G.
AU - Firestein, Bonnie L.
N1 - Funding Information:
This work was supported by National Institute of Mental Health grant R01 MH062440 (to LB), a National Alliance for Research on Schizophrenia and Depression 2012 Marion G. Nicholson Distinguished Investigator Award (to BLF), a grant from the Human Genetics Institute of New Jersey (to BLF), and in part, by National Science Foundation grants IBN-0919747 and IBN-1353724 (to BLF). KH was supported in part by National Institutes of Health Initiative for Maximizing Student Development Grant 2R25 GM55145 and NSF DGE 0801620 , and KH and CMC were supported in part by National Institutes of Health Biotechnology Training Grant T32 GM008339-20 . KGP and SGC were supported by NIH R00 award NS051401-42 (to KGP). AKB, AYF, and ND received funding from the Aresty Undergraduate Research Fellowship and AKB and ND were awarded Rutgers University School of Arts and Sciences Undergraduate Research Fellowships.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/12
Y1 - 2020/12
N2 - Abnormal dendritic arbor development has been implicated in a number of neurodevelopmental disorders, such as autism and Rett syndrome, and the neuropsychiatric disorder schizophrenia. Postmortem brain samples from subjects with schizophrenia show elevated levels of NOS1AP in the dorsolateral prefrontal cortex, a region of the brain associated with cognitive function. We previously reported that the long isoform of NOS1AP (NOS1AP-L), but not the short isoform (NOS1AP-S), negatively regulates dendrite branching in rat hippocampal neurons. To investigate the role that NOS1AP isoforms play in human dendritic arbor development, we adapted methods to generate human neural progenitor cells and neurons using induced pluripotent stem cell (iPSC) technology. We found that increased protein levels of either NOS1AP-L or NOS1AP-S decrease dendrite branching in human neurons at the developmental time point when primary and secondary branching actively occurs. Next, we tested whether pharmacological agents can decrease the expression of NOS1AP isoforms. Treatment of human iPSC-derived neurons with D-serine, but not clozapine, haloperidol, fluphenazine, or GLYX-13, results in a reduction in endogenous NOS1AP-L, but not NOS1AP-S, protein expression; however, D-serine treatment does not reverse decreases in dendrite number mediated by overexpression of NOS1AP isoforms. In summary, we demonstrate how an in vitro model of human neuronal development can help in understanding the etiology of schizophrenia and can also be used as a platform to screen drugs for patients.
AB - Abnormal dendritic arbor development has been implicated in a number of neurodevelopmental disorders, such as autism and Rett syndrome, and the neuropsychiatric disorder schizophrenia. Postmortem brain samples from subjects with schizophrenia show elevated levels of NOS1AP in the dorsolateral prefrontal cortex, a region of the brain associated with cognitive function. We previously reported that the long isoform of NOS1AP (NOS1AP-L), but not the short isoform (NOS1AP-S), negatively regulates dendrite branching in rat hippocampal neurons. To investigate the role that NOS1AP isoforms play in human dendritic arbor development, we adapted methods to generate human neural progenitor cells and neurons using induced pluripotent stem cell (iPSC) technology. We found that increased protein levels of either NOS1AP-L or NOS1AP-S decrease dendrite branching in human neurons at the developmental time point when primary and secondary branching actively occurs. Next, we tested whether pharmacological agents can decrease the expression of NOS1AP isoforms. Treatment of human iPSC-derived neurons with D-serine, but not clozapine, haloperidol, fluphenazine, or GLYX-13, results in a reduction in endogenous NOS1AP-L, but not NOS1AP-S, protein expression; however, D-serine treatment does not reverse decreases in dendrite number mediated by overexpression of NOS1AP isoforms. In summary, we demonstrate how an in vitro model of human neuronal development can help in understanding the etiology of schizophrenia and can also be used as a platform to screen drugs for patients.
KW - Antipsychotic medication
KW - Arborization
KW - D-Serine
KW - Morphology
KW - NOS1AP
KW - hiPSC-derived neurons
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U2 - 10.1016/j.mcn.2020.103562
DO - 10.1016/j.mcn.2020.103562
M3 - Article
C2 - 32987141
AN - SCOPUS:85092097875
SN - 1044-7431
VL - 109
JO - Molecular and Cellular Neurosciences
JF - Molecular and Cellular Neurosciences
M1 - 103562
ER -