Year

2020

Degree Name

Doctor of Philosophy

Department

School of Medicine

Abstract

Schizophrenia patients have altered neuronal connectivity, while the causal factor is not fully understood. Most antipsychotic drugs possess dopamine D2 receptor (D2R) antagonist property as a therapeutic target for reducing dopamine hyperactivity in schizophrenia. It is, however, not known whether the blockage of D2R is beneficial to neural connectivity. This study aimed to investigate the mechanisms of neurite lesion induced by D2R overactivation and prevention of such lesion by changing the D2R downstream signaling.

Disrupted in schizophrenia 1 (DISC1) is a genetic risk factor for a wide range of psychiatric illnesses, including schizophrenia. DISC1 is a multifunctional scaffold protein that regulates neurogenesis and neural development in the adult brain. The excessive D2R-DISC1 complex is observed in the post-mortem brain of schizophrenia patients. However, the role of D2R-DISC1 complex in neurite outgrowth is unknown. The aim of Chapter 2 was to study whether neurite lesion induced by D2R overactivation is through the D2R-DISC1 complex. This study applied fluorescence resonance energy transfer (FRET) technique to quantify the interaction between D2R and DISC1 in primary cortical neurons. D2R specific agonist quinpirole increased the interaction of D2R and DISC1 by over activating D2R in primary cortical neurons. Furthermore, the excessive D2R-DISC1 complex reduced glycogen synthase kinase β (GSK-3β) phosphorylation. The increased D2R-DISC1 complex formation in conjunction with the decreased GSK-3β phosphorylation resulted in neurite impairment of cortical neurons. The antipsychotics haloperidol and aripiprazole disrupted the excessive formation of the D2R-DISC1 complex caused by D2R overactivation. However, only aripiprazole could reverse the downregulation of phosphorylated GSK3β caused by quinpirole. Aripiprazole displayed better preventative effect than haloperidol on neurite lesion induced by quinpirole, suggesting that aripiprazole and haloperidol may affect neuroplasticity via different signaling pathways. Also, both haloperidol and aripiprazole failed to rescue neurite lesion of primary cortical neurons from DISC1 mutant mice. In summary, the normal D2R-DISC1 complex signaling is critical for neurite outgrowth.

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.