Nitric oxide synthase 1 adaptor protein as a target for treatment of schizophrenia
Description
TitleNitric oxide synthase 1 adaptor protein as a target for treatment of schizophrenia
Date Created2018
Other Date2018-01 (degree)
Extent1 online resource (vi, 49 p. : ill.)
DescriptionSchizophrenia (SCZ) is a severe mental illness that affects 1% of the U.S. population. Antipsychotic medications are ineffective for many patients with SCZ, and N-methyl D-aspartate receptor (NMDAR) agonists may be potential treatments. Nitric oxide synthase 1 adaptor protein (NOS1AP) is overexpressed in the dorsolateral prefrontal cortex of patients with SCZ. NOS1AP negatively regulates NMDAR signaling and reduces dendrite branching in vitro, reproducing the abnormalities in dendrite branching observed in patients with SCZ. Here, we investigate 1) the effects of antipsychotics and NMDAR agonists on function and expression of NOS1AP, dopamine receptor D2 (D2), and disrupted in SCZ 1 (DISC1), and 2) the potential of NOS1AP as a biomarker for SCZ using human buccal cells to screen for NOS1AP expression. First, we treated cortical neurons with antipsychotics or NMDAR agonists (GLYX-13 and D-serine) for 24 hours and used Western blot analysis to determine the effects of these drugs on NOS1AP expression. Using Sholl analysis, we analyzed effects on dendrite branching in cortical rat neurons overexpressing NOS1AP. Additionally, we administered haloperidol or D-serine to male and female Sprague Dawley rats via intraperitoneal injection for 12 days. We used Western blot analysis to determine the effects of treatment on cortical expression of NOS1AP, D2 receptor, and DISC1. Antipsychotics did not affect NOS1AP expression or dendrite branching in vitro, while GLYX-13 and D-serine reduced expression and corrected NOS1AP-mediated reductions in dendrite branching. Haloperidol significantly reduced D2 receptor expression in male, but not female, rats. Importantly, D-serine reduced NOS1AP expression in male, but not female, rats and had no effect on D2 receptor expression. D-serine also showed sex-specific effects on expression of disrupted in SCZ 1 (DISC1). To investigate the potential of NOS1AP as a biomarker for SCZ, we first collected buccal swabs from healthy control subjects. Using Western blot analysis, we confirmed that NOS1AP is consistently expressed in buccal cells, which had never before been investigated. We then assessed buccal cell NOS1AP expression in patients with SCZ and genotyped patients and healthy control subjects for single nucleotide polymorphisms (SNPs) in NOS1AP. Our data indicate that NOS1AP expression may be elevated in patients with SCZ who show rare disease-associated alleles in NOS1AP. Taken together, our data show for the first time that 1) D-serine influences the function and expression of NOS1AP, D2 receptor, and DISC1 in a sex-specific manner, and 2) buccal cell NOS1AP may be a biomarker for SCZ.
NoteM.S.
NoteIncludes bibliographical references
Noteby Kirsten Svane
Genretheses, ETD graduate
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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