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The role of the serotonin reuptake transporter on cytoskeletal drebrin A expression in dendritic spines: Implications for neuropsychiatric disorders

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thesis
posted on 2022-07-28, 04:48 authored by Chaji, Daniel

Knockout of the serotonin reuptake transporter (SERT) in murine animals has been shown to model various neuropsychiatric disorders such as major depressive disorder, autism spectrum disorder, and substance use disorder. Moreover, evidence suggests that abnormalities in glutamatergic synapses at the level of dendritic spines may be involved in the aetiology of these disorders. This thesis investigated the extent to which the SERT knockout model adequately parallels dendritic spine abnormalities associated with these disorders. This investigation focused on an oft-neglected F-actin binding protein highly-localised to dendritic spines, drebrin A, because any changes to dendritic spines would result in changes to drebrin expression, alongside more common markers for assessing synaptic activity, PSD95 and synaptophysin. The frontal cortex was assessed across the three SERT knockout genotypes at a pre-weaning timepoint and at early adulthood. Results indicated a pattern towards reduced expression for drebrin, PSD95 and synaptophysin at the mRNA level, as well as reduced synaptophysin expression at the protein level, at the pre-weaning stage among SERT knockout animals. No synaptic abnormalities were observed at early adulthood. These abnormalities during development were mirrored by a substantial reduction in dendritic spine density on SERT knockout mature cortical neurons in vitro. The recently developed and highly-sensitive in situ hybridization method for assessing mRNA expression in tissue, RNAscope®, was also optimised for drebrin mRNA. Altogether, the results suggested that serotonergic activity influences dendritic spine density and synaptic marker expression insofar as the serotonin system acts as a neuromodulator of the glutamate system, which coincides with the peri- and post- natal development period. These effects seemed to result in aberrations to glutamatergic neurotransmission and dendritic spine activity, which may be contribute to the mechanisms involved in neuropsychiatric disorder pathophysiology. Finally, a model involving activation of the 5-HT2A receptor to partly explain the findings in this thesis, is proposed.

History

Copyright Date

2020-01-01

Date of Award

2020-01-01

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Neuroscience

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Masters

Degree Name

Master of Science

ANZSRC Type Of Activity code

1 PURE BASIC RESEARCH

Victoria University of Wellington Item Type

Awarded Research Masters Thesis

Language

en_NZ

Victoria University of Wellington School

School of Biological Sciences

Advisors

Ellenbroek, Bart; Day, Darren