@phdthesis{Candemir2018,
  author    = {Candemir, Esin},
  title     = {Involvement of neuronal nitric oxide synthase (NOS-I) PDZ interactions in neuropsychiatric disorders},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151194},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {Neuronal nitric oxide (NO) synthase (NOS-I) and its adaptor protein (NOS1AP) have been repeatedly and consistently associated with neuropsychiatric disorders in several genetic association and linkage studies, as well as functional studies. NOS-I has an extended PDZ domain which enables it to interact with postsynaptic density protein 95 (PSD-95) bringing NOS-I in close proximity to NMDA receptors. This interaction allows NMDA receptor activity dependent calcium-influx to activate NOS-I, linking NO synthesis to regulation of glutamatergic signaling pathways. NOS1AP is a PDZ-domain ligand of NOS-I and has been proposed to compete with PSD-95 for NOS-I interaction. Studies performed on post-mortem brain tissues have shown increased expression of NOS1AP in patients with schizophrenia and bipolar disorder, suggesting that increased NOS-I/NOS1AP interactions might be involved in neuropsychiatric disorders possibly through disruption of NOS-I PDZ interactions. Therefore, I have investigated the involvement of NOS-I in different endophenotypes of neuropsychiatric disorders by targeting its specific PDZ interactions in vitro and in vivo. To this end, I used recombinant adeno-associated virus (rAAV) vectors expressing NOS1AP isoforms/domains (NOS1AP-L: full length NOS1AP; NOS1AP-LC20: the last 20 amino acids of NOS1AP-L, containing the PDZ interaction motif suggested to stabilize interaction with NOS-I; NOS1AP-LΔC20: NOS1AP-L lacking the last 20 amino acids; NOS1AP-S: the short isoform of NOS1AP), residues 396-503 of NOS1AP-L (NOS1AP396-503) encoding the full NOS-I interaction domain, and N-terminal 133 amino acids of NOS-I (NOS-I1-133) encoding for the extended PDZ-domain. Neuropsychiatric disorders involve morphological brain changes including altered dendritic development and spine plasticity. Hence, I have examined dendritic morphology in primary cultured hippocampal and cortical neurons upon overexpression of constructed rAAV vectors. Sholl analysis revealed that overexpression of NOS1AP-L and NOS1AP-LΔC20 mildly reduced dendritic length/branching. Moreover, overexpression of all NOS1AP isoforms/domains resulted in highly altered spine plasticity including significant reduction in the number of mature spines and increased growth of filopodia. These findings suggest that NOS1AP affects dendritic growth and development of dendritic spines, which may involve both, increased NOS-I/NOS1AP interaction as well as interaction of NOS1AP with proteins other than NOS-I. Interestingly, the observed alterations in dendritic morphology were reminiscent of those observed in post-mortem brains of patients with neuropsychiatric disorders. Given the dendritic alterations in vitro, I have examined, whether disruption of NOS-I PDZ interaction would also result in behavioral deficits associated with neuropsychiatric disorders. To this end, rAAV vectors expressing NOS1AP-L, NOS1AP396-503, NOS-I1-133, and mCherry were stereotaxically delivered to the dorsal hippocampus of 6-week-old male C57Bl/6J mice. One week after surgery, mice were randomly separated into two groups. One of those groups underwent three weeks of chronic mild stress (CMS). Afterwards all mice were subjected to a comprehensive behavioral analysis. The findings revealed that overexpression of the constructs did not result in phenotypes related to anxiety or depression, though CMS had an anxiolytic effect independent of the injected construct. Mice overexpressing NOS-I1-133, previously shown to disrupt NOS-I/PSD-95 interaction, showed impaired spatial memory, sensorimotor gating, social interaction, and increased locomotor activity. NOS1AP overexpressing mice showed mild impairments in sensorimotor gating and spatial working memory and severely impaired social interaction. NOS1AP396-503 overexpressing mice also showed impaired social interaction but enhanced sensorimotor gating and reduced locomotor activity. Taken together, these behavioral findings indicate an involvement of NOS-I PDZ interactions in phenotypes associated with positive symptoms and cognitive deficits of psychotic disorders. In summary, this study revealed an important contribution of NOS-I protein interactions in the development of endophenotypic traits of neuropsychiatric disorders, in particular schizophrenia, at morphological and behavioral levels. These findings might eventually aid to a better understanding of NOS-I-dependent psychopathogenesis, and to develop pharmacologically relevant treatment strategies.},
  subject      = {Stickstoffmonoxid-Synthase},
  language  = {en}
}
@phdthesis{Link2011,
  author    = {Link, Martin Benedikt [jetzt: Sittl, Martin]},
  title     = {Die Rolle der neuronalen Stickstoffmonoxid-Synthase im Herzen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69252},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {Diese Arbeit zeigt, dass die spezifische Inhibition der neuronalen NO-Synthase zu einer Reduktion der myokardialen {\"O}konomie f{\"u}hrt. Umgekehrt l{\"a}sst sich postulieren, dass die Produktion von Stickstoffmonoxid durch die nNOS eine gesteigerte Effizienz des Herzmuskelgewebes bewirkt.},
  subject      = {Stickstoffmonoxid-Synthase},
  language  = {de}
}
@phdthesis{Hoetten2007,
  author    = {H{\"o}tten, Stefanie Brigitte},
  title     = {Atheroprotektive Effekte der neuronalen Stickstoffmonoxid-Synthase in Apolipoprotein-E-Knockout-M{\"a}usen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-22093},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {In dieser Arbeit wurde die Rolle der neuronalen Stickstoffmonoxid-Synthase in der spontanen Atheroskleroseentwicklung untersucht. Die Untersuchungen wurden an Apolipoprotein E-Knockout /neuronale Stickstoffmonoxid-Synthase-Knockout-M{\"a}usen und Apolipoprotein E-Knockout-M{\"a}usen durchgef{\"u}hrt, die zuvor 14 bzw. 24 Wochen mit einer ‚western-type'-Di{\"a}t gef{\"u}ttert worden sind. Durch eine immunhistochemische Analyse konnte zun{\"a}chst gezeigt werden, dass neuronale Stickstoffmonoxid-Synthase in Plaques von Apolipoprotein E-Knockout M{\"a}usen exprimiert wird. Nach 14 Wochen ‚western-type'- Di{\"a}t zeigten m{\"a}nnliche Apolipoprotein E-Knockout/neuronale Stickstoffmonoxid-Synthase-Knockout Tiere eine signifikante Zunahme der \%-L{\"a}sionsfl{\"a}che um 66\%. Im Gegensatz dazu war die \%-L{\"a}sionsfl{\"a}che der weiblichen Apolipoprotein E-Knockout/neuronale Stickstoffmonoxid-Synthase-Knockout Tiere nach 14 Wochen unver{\"a}ndert, zeigte aber nach 24 Wochen eine signifikante Zunahme um 32 \%. Aortengesamtfl{\"a}che, K{\"o}rpergewicht und Plasmacholesterinspiegel waren zwischen gleichgeschlechtlichen Tieren der verschiedenen Genotypen unver{\"a}ndert. Der mittlere arterielle Blutdruck der weiblichen Apolipoprotein E-Knockout/neuronale Stickstoffmonoxid-Synthase-Knockout Tiere war signifikant reduziert, bei den m{\"a}nnlichen Tieren fand sich kein Blutdruckunterschied. Dieser Befund k{\"o}nnte eine m{\"o}gliche Erkl{\"a}rung f{\"u}r die verz{\"o}gerte Plaqueentwicklung bei weiblichen Apolipoprotein E-Knockout/neuronale Stickstoffmonoxid-Synthase-Knockout Tieren darstellen. Die Ergebnisse der vorliegenden Arbeit zeigen, dass ein Mangel an neuronaler Stickstoffmonoxid-Synthase zu einer deutlichen Zunahme der Atherosklerose f{\"u}hrt, so dass ein atheroprotektiver Effekt der neuronalen Stickstoffmonoxid-Synthase angenommen werden kann.},
  language  = {de}
}