Improving Outcomes in First Episode Psychosis: The Role of Genetic Variation of NPAS3

• Author / Creator

  Luoma, Leiah M

• NPAS3 encodes a transcription factor of the bHLH-PAS family, which has been robustly associated with neurodevelopmental and psychiatric disorders with intellectual disability as a common feature. NPAS3 was initially discovered as a schizophrenia-associated gene in a family with a translocation breaking only NPAS3. Since then, deletions encompassing NPAS3 have been associated with neurodevelopmental disorders such as holoprosencephaly, holoprosencephaly microforme and Sotos syndrome. SNPs linked to, and within, NPAS3 have been associated with neuropsychiatric disorders, including schizophrenia and bipolar disorder, as well as antipsychotic responsiveness. A common feature of all of these disorders is intellectual disability. Deletion of NPAS3 in mice results in marked behavioural and neuroanatomical phenotypes reminiscent of neuropsychiatric disorders, including increased anxiety, altered behavior and deficits in learning and memory. Further, deficits in neurodevelopment in utero resulting in reduced interneuron number, smaller cortical volume, increased ventricles and altered cerebellar foliation, as well as deficits in adult neurogenesis in the dentate gyrus of the hippocampus, have been observed. Despite the robustness of the evidence that NPAS3 is associated with neuropsychological function and neuropsychiatric dysfunction, its molecular function is not well characterized. Here, I set out to functionally characterize NPAS3 as a transcription factor of the bHLH-PAS family. I assessed its ability to interact with its presumed obligate heterodimeric partner, ARNT, as well as its ability to directly bind and regulate genes it has been found to genetically regulate. I have determined that NPAS3 does functionally interact with ARNT to regulate two target genes directly: VGF and TXNIP, both of which have functions relevant to cell survival and neuronal functions. Through the assays developed to characterize NPAS3 function, I have characterized the function of its predicted domains and found them to participate in DNA binding, protein::protein interaction and transactivation, consistent with the categorization of NPAS3 as a bHLH-PAS transcription factor. Assessment of NPAS3 function at the cellular level was performed and NPAS3 expression at the mRNA level was found to respond to soluble factors, as well as cell contact, suggesting a role of NPAS3 in environmental response. As the disorders with which NPAS3 has been associated share a common feature of intellectual disability, a collaborative study was undertaken to assess the contribution of NPAS3 variation to normal variation in neurocognition in order to understand its role in neuropsychological function, both normal and disordered. To that end, we have assessed the contribution of exonic variation of NPAS3 to cognitive function in a cross-sectional population of Western Canadian young adults. The minor alleles of a three SNP haplotype within exon 12 of NPAS3 were found to be associated with worse performance on a test of verbal working memory, and a trend was observed with generally reduced cognitive function, as assessed by the Screen for Cognitive Impairment in Psychiatry. Taken together, these data expand our understanding of the role of NPAS3 in normal cognitive functioning and neuropsychiatric dysfunction. NPAS3 has been found to directly regulate two genes with roles in neuronal survival, stress/injury response and metabolic balance. These data support the role of NPAS3 in the survival of proliferating neuroprogenitors during neurodevelopment and neurogenic processes, which can be predicted to contribute to the intellectual disability observed when NPAS3 expression is reduced or lost.

• Subjects / Keywords

  • bHLH-PAS
  • Psychosis
  • Gene Regulation
  • NPAS3
  • ARNT
  • Genetics
  • Cognition
  • Transcription Factor

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R30G3HF0V

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.