The involvement of DARPP-32 in the pathophysiology of schizophrenia

Haitao Wang, Mohd Farhan, Jiangping Xu, Philip Lazarovici and Wenhua Zheng _

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Oncotarget. 2017; 8:53791-53803. https://doi.org/10.18632/oncotarget.17339

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Haitao Wang1,2,*, Mohd Farhan1,*, Jiangping Xu2, Philip Lazarovici3 and Wenhua Zheng1

1Faculty of Health Sciences, University of Macau, Taipa, Macau, China

2School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China

3School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

*These authors contributed equally to this work

Correspondence to:

Wenhua Zheng, email: wenhuazheng@umac.mo

Keywords: schizophrenia, DARPP-32, dopamine, cAMP, glutamate

Received: February 23, 2017     Accepted: April 12, 2017     Published: April 21, 2017


Schizophrenia is one of the most devastating heterogeneous psychiatric disorders. The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia based on neurochemical evidences of elevated brain striatal dopamine synthesis capacity and increased dopamine release in response to stress. Dopamine and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000 (DARPP-32) is a cytosolic protein highly enriched in the medium spiny neurons of the neostriatum, considered as the most important integrator between the cortical input and the basal ganglia, and associated with motor control. Accumulating evidences has indicated the involvement of DARPP-32 in the development of schizophrenia; i. DARPP-32 phosphorylation is regulated by several neurotransmitters, including dopamine and glutamate, neurotransmitters implicated in schizophrenia pathogenesis; ii. decrease of both total and phosphorylated DARPP-32 in the prefrontal cortex are observed in schizophrenic animal models; iii. postmortem brain studies indicated decreased expression of DARPP-32 protein in the superior temporal gyrus and dorsolateral prefrontal cortex in patients with schizophrenia; iv. DARPP-32 phosphorylation is increased upon therapy with antipsychotic drugs, such as haloperidol and risperidone which improve behavioral performance in experimental animal models and patients; v. Genetic analysis of the gene coding for DARPP-32 propose an association with schizophrenia. Cumulatively, these findings implicate DARPP-32 protein in schizophrenia and propose it as a potential therapeutic target. Here, we summarize the possible roles of DARPP-32 during the development of schizophrenia and make some recommendations for future research. We propose that DARPP-32 and its interacting proteins may serve as potential therapeutic targets in the treatment of schizophrenia.

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