Schizophrenia susceptibility gene dysbindin regulates glutamatergic and dopaminergic functions via distinctive mechanisms in Drosophila

Shao, L., Shuai, Y., Wang, J., Feng, S., Lu, B., Li, Z., Zhao, Y., Wang, L., Zhong, Y. (2011) Schizophrenia susceptibility gene dysbindin regulates glutamatergic and dopaminergic functions via distinctive mechanisms in Drosophila. Proceedings of the National Academy of Sciences of the United States of America, 108 (46). pp. 18831-18836. ISSN 00278424 (ISSN)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/22049342
DOI: 10.1073/pnas.1114569108

Abstract

The dysfunction of multiple neurotransmitter systems is a striking pathophysiological feature of many mental disorders, schizophrenia in particular, but delineating the underlying mechanisms has been challenging. Here we show that manipulation of a single schizophrenia susceptibility gene, dysbindin, is capable of regulating both glutamatergic and dopaminergic functions through two independent mechanisms, consequently leading to two categories of clinically relevant behavioral phenotypes. Dysbindin has been reported to affect glutamatergic and dopaminergic functions as well as a range of clinically relevant behaviors in vertebrates and invertebrates but has been thought to have a mainly neuronal origin. We find that reduced expression of Drosophila dysbindin (Ddysb) in presynaptic neurons significantly suppresses glutamatergic synaptic transmission and that this glutamatergic defect is responsible for impaired memory. However, only the reduced expression of Ddysb in glial cells is the cause of hyperdopaminergic activities that lead to abnormal locomotion and altered mating orientation. This effect is attributable to the altered expression of a dopamine metabolic enzyme, Ebony, in glial cells. Thus, Ddysb regulates glutamatergic transmission through its neuronal function and regulates dopamine metabolism by regulating Ebony expression in glial cells.

Item Type: Paper
Uncontrolled Keywords: Dystrobrevin binding protein 1 Glia Glutamate Drosophila protein dysbindin glutamic acid 3' untranslated region allele animal cell article brain function controlled study dopamine metabolism dopaminergic transmission Drosophila genetic susceptibility glia cell immunohistochemistry locomotion mating memory memory disorder nerve cell nonhuman phenotype postsynaptic potential presynaptic nerve priority journal protein expression protein localization regulatory mechanism schizophrenia signal transduction synaptic transmission transposon
Subjects: organism description > animal > insect > Drosophila
diseases & disorders > mental disorders > schizophrenia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
CSHL Authors:
Communities: CSHL labs > Zhong lab
CSHL Post Doctoral Fellows
Depositing User: CSHL Librarian
Date: 2011
Date Deposited: 29 Mar 2012 19:48
Last Modified: 03 Jan 2018 17:23
Related URLs:
URI: http://repository.cshl.edu/id/eprint/25598

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