Schizophrenia a disease mediated by neuroinflammation, neurotransmitters, or both

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Copyright: Fillman, Stu
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Abstract
Schizophrenia is a disease characterized by both positive symptoms such as hallucinations and delusions as well as negative symptoms, including cognitive and behavior issues which may arise from either neurodevelopmental or neurodegenerative causes. These causes may involve either neurotransmitter systems including glutamate, dopamine, GABA and serotonin or an ongoing neuroinflammatory process. In this body we used samples from the dorsolateral prefrontal cortex (DLPFC) of 68 individuals throughout development and 74 individuals from a matched case control cohort. We examined the GABAA receptor as well as the serotonin receptor mRNA through quantitative-PCR. Furthermore to establish exactly what alterations in the GABAA receptor occur in schizophrenia we supplemented our developmental studies with qPCR and in vitro autoradiography. To examine more broadly changes which occur in the entire DLPFC we perform RNA-Seq in a subcohort of 20 individuals with schizophrenia and their matched controls. Targets were further characterized using immunohistochemistry, western blotting and qPCR. GABAA receptor mRNA expression changes extensively through development with two programs occurring, subunits with decreasing expression and a corresponding group with a more dynamic path. In schizophrenia there is an increase in in vitro binding to the GABAA receptor at both the GABA and benzodiazepine binding sites which are not linked to broad increases in subunit mRNA expression but do correlate with α4 and γ2S subunit mRNAs respectively. Serotonin receptors also change broadly throughout development but with concurrent inhibitory and excitatory receptors mRNA expression increases indicating a systemic balance. Broadly in the DLPFC of individuals with schizophrenia there was an increase in markers of neuroinflammation, including cytokines (IL-6, IL-8), associated molecules (SERPINA3) and microglial cells. This change was driven by a group comprising of 40% of the individuals with schizophrenia. Our results show that both the GABAA and serotonin receptor systems have a protracted developmental program but changes in either system s normal development cannot explain those observed in schizophrenia. The GABAA receptor elevated binding displays weak associations with subunit mRNA levels, and is likely post-translational. The serotonin system s dynamic changes indicate differential effects of drugs targeting these receptors throughout development. Finally, in schizophrenia our biological subgroup showing or displaying elevated neuroinflammation provides a novel therapeutic target for interventions.
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Author(s)
Fillman, Stu
Supervisor(s)
Shannon Weickert, Cynthia
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Publication Year
2013
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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