Decreased Expression of the Protein Orhodenticle Homeobox 2 (Otx2) in Individuals With Schizophrenia: A Postmortem Investigation
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CitationArdelt, Magdalena. 2016. Decreased Expression of the Protein Orhodenticle Homeobox 2 (Otx2) in Individuals With Schizophrenia: A Postmortem Investigation. Master's thesis, Harvard Extension School.
AbstractThe purpose of this thesis was to determine if the amount of the protein Orthodenticle homeobox 2 (Otx2) is reduced in individuals with schizophrenia. Otx2 is a transcription factor that plays an essential role in the development and maintenance of a specific class of GABAergic interneurons that express the protein parvalbumin (PV+ GABAergic interneurons). In addition, Otx2 participates in the development and maintenance of perineuronal nets. Perineuronal nets are important extracellular matrix structures that encompass PV+ GABAergic interneurons and facilitate their proper functioning (Beurdeley, 2012). It is speculated that perineuronal net structural abnormalities can lead to impaired PV+ GABAergic interneuron function and these impairments contribute to the manifestation of the condition schizophrenia (Berretta et al., 2015). Because Otx2 is needed for both healthy PV+ GABAergic interneurons and functional perineuronal nets, we postulated that insufficient levels of Otx2 in the amygdala might contribute to impaired GABAergic neurotransmission as exhibited in individuals with schizophrenia. Interestingly, PV+ GABAergic interneurons that require Otx2 do not produce Otx2. Recently, it was shown in mouse models that Otx2 is made in the choroid plexus, released into the cerebral spinal fluid and carried to cortical areas where it becomes available to be used by neurons (Spattazza et al., 2013). Similarly, in human postmortem samples, we observed the presence of Otx2 in the choroid plexus (Pantazopoulos et al., Manuscript in Preparation). Furthermore, we observed a novel phenomenon in human samples; Otx2 was found in vesicles in the cerebral spinal fluid and in the amygdala samples. We hypothesized that PV+ GABAergic interneurons located in the amygdala obtained Otx2 from the choroid plexus by delivery in vesicles via the cerebral spinal fluid. Based on this observation and building on current scientific understanding of schizophrenia, we proposed that there would be fewer vesicles in the amygdala samples donated by individuals with schizophrenia compared to samples donated by healthy controls. To test this hypothesis, the number of vesicles that contained Otx2 in amygdala samples donated by individuals diagnosed with schizophrenia (n=15) was compared to the number of vesicles that contained Otx2 in amygdala samples donated by healthy control donors (n=15). The results showed that there was not a significant decrease in the number of vesicles that contained Otx2 in amygdala samples donated by individuals with schizophrenia compared to samples donated by healthy controls (p-value > 0.05). However, an enzyme linked immunosorbent assay (ELISA) was performed to measure the amount of Otx2 inside vesicles and a significant decrease in the amount of Otx2 was observed in cerebral spinal fluid samples donated by individuals with schizophrenia (n=11) compared to healthy controls (n=15), (p-value < 0.05). In conclusion, this thesis work honed in on three major ideas. First, the method of delivery of Otx2 to neurons in the amygdala appeared to be via vesicles filled with Otx2, which originated in the choroid plexus. Second, there was not a decrease in the number of vesicles that contained Otx2 in samples from individuals with schizophrenia. Finally, preliminary experiments that measured Otx2 protein concentration inside the vesicles indicated that the amount of Otx2 contained in the vesicles was reduced in samples donated by individuals with schizophrenia compared to healthy controls. These finding are potential first steps in the development of a bioassay for the molecular characterization of the condition of schizophrenia.
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