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Schizophrenia Susceptibility Gene Dysbindin Regulates Glutamatergic and Dopaminergic Functions Via Distinctive Mechanisms in Drosophila

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Schizophrenia Susceptibility Gene Dysbindin Regulates Glutamatergic and Dopaminergic Functions Via Distinctive Mechanisms in Drosophila Schizophrenia susceptibility gene dysbindin regulates glutamatergic and dopaminergic functions via distinctive mechanisms in Drosophila Lisha Shaoa, Yichun Shuaia, Jie Wanga, Shanxi Fenga, Binyan Lua, Zuo Lia, Yukai Zhaoa, Lianzhang Wanga, and Yi Zhonga,b,1 aSchool of Life Sciences, Tsinghua University, Beijing 100084, People’s Republic of China; and bCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724 Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 7, 2011 (received for review September 4, 2011) The dysfunction of multiple neurotransmitter systems is a striking dysbindin expression has been reported in the prefrontal cortex pathophysiological feature of many mental disorders, schizophrenia and hippocampus of schizophrenia patients (10, 11). Although it is in particular, but delineating the underlying mechanisms has been a null mutant, the spontaneously occurring deletion in the mouse challenging. Here we show that manipulation of a single schizo- homolog of DTNBP1 (7) leads to a range of schizophrenia-related phrenia susceptibility gene, dysbindin, is capable of regulating both pathophysiological and behavioral phenotypes, including reduced glutamatergic and dopaminergic functions through two indepen- glutamatergic transmission, abnormalities in dopaminergic ac- dent mechanisms, consequently leading to two categories of clini- tivities, locomotor hyperactivity, social withdrawal, and memory compromise (12, 13). cally relevant behavioral phenotypes. Dysbindin has been reported – to affect glutamatergic and dopaminergic functions as well as a This study of the Drosophila mutant demonstrates that a 30 range of clinically relevant behaviors in vertebrates and inverte- 40% reduction in Ddysb expression is capable of recapitulat- brates but has been thought to have a mainly neuronal origin. We ing major features of schizophrenia-related pathophysiological “sandy” find that reduced expression of Drosophila dysbindin (Ddysb) in pre- changes observed in the null mutant of the so-called mouse. Genetic manipulation allowed us to reveal distinct func- synaptic neurons significantly suppresses glutamatergic synaptic tions of Ddysb in neurons and in glial cells. Disruption of Ddysb transmission and that this glutamatergic defect is responsible for function in neurons is responsible for hypoglutamatergic trans- impaired memory. However, only the reduced expression of Ddysb mission and subsequent memory defects, whereas disruption of in glial cells is the cause of hyperdopaminergic activities that lead to Ddysb function in glial cells causes hyperdopaminergic activity and abnormal locomotion and altered mating orientation. This effect is locomotor hyperactivity via the reduction of the protein Ebony. attributable to the altered expression of a dopamine metabolic en- zyme, Ebony, in glial cells. Thus, Ddysb regulates glutamatergic Results transmission through its neuronal function and regulates dopamine Characterization of the Ddysb Mutant. The Ddysb mutant studied metabolism by regulating Ebony expression in glial cells. here is a pBace01028 mutant carrying a piggyBac transposon in the 3′ UTR of Ddysb (Fig. 1A). Western blotting revealed that Ddysb dystrobrevin binding protein 1 | glutamate | glia expression in the adult head was reduced by ∼40% in this mutant (Fig. 1B). Immunohistochemistry also showed a consistent re- chizophrenia is a debilitating mental disorder with intricate duction of Ddysb signals in the mutant brain (Fig. S1A). In ac- Setiology and multidimensional pathophysiological and clinical cordance with a recent report (14), these results suggest that features. Pathophysiologically, multiple neurotransmitter systems, pBace01028 is a hypomorphic allele of Ddysb and thus is referred to including glutamate, dopamine, GABA, and serotonin, are dis- hereafter as “dysb1.” turbed in this morbid condition (1). Accordingly, schizophrenia has We first looked at pathophysiology-related changes, i.e., glu- multiple clinical characteristics, including positive symptoms, nega- tamatergic and dopaminergic activities. The two-electrode volt- tive symptoms, and cognitive impairments (2). However, how an age-clamp method was used to assay excitatory junctional currents imbalance of multiple neurotransmitter systems evolves and how the (EJCs) of glutamatergic synaptic transmission at the well-char- pathophysiological abnormalities give rise to the clinical features acterized larval neuromuscular junction (NMJ) (15). The dysb1 remain to be elucidated. Despite the complicated pathophysiology mutant showed significantly attenuated EJCs at various extracel- and associated symptoms, evidence is mounting that genetic factors lular calcium concentrations (Fig. 1C) without significant morphol- contribute substantially to the development and expression of schizo- ogical changes; this result is consistent with a recent indepen- phrenia (3). Human genetic studies have identifiedaplethoraof dent study (14). To assay how dopamine activity might be affected, NEUROSCIENCE candidate genes linked to susceptibility for this disease (4). Notably, we measured the dopamine level in the heads of adult flies using many susceptibility genes act by regulating the function or homeo- ELISA (16). The dopamine concentration in dysb1 mutant heads stasis of multiple neurotransmitter systems (5). Therefore, genetic was around twofold of that in WT flies (Fig. 1D). Therefore, re- manipulation of these susceptibility genes will help disclose the duced Ddysb expression leads to both hypoglutamatergic and mechanisms underlying the genetic regulation of neurotransmitter hyperdopaminergic activities. systems as well as related behaviors and in turn will increase our For pathophysiology-relevant behavioral phenotypes, we fo- understanding of the pathogenesis of the disease per se. cused mainly on learning task and locomotor activity, because For this purpose, the current study began with an analysis of a Drosophila mutant of dysbindin (Ddysb), an ortholog of the hu- man schizophrenia susceptibility gene, dystrobrevin binding protein Author contributions: L.S., Y.S., J.W., S.F., B.L., and Y. Zhong designed research; L.S., Y.S., 1 (DTNBP1, also known as “dysbindin”). The DTNBP1-encoded J.W., S.F., B.L., Z.L., Y. Zhao, and L.W. performed research; L.S., Y.S., J.W., S.F., Z.L., and dysbindin-1 was identified initially as a member of the dystrophin- Y. Zhao analyzed data; and L.S., Y.S., B.L., and Y. Zhong wrote the paper. associated protein complex (6) and later as a member of the The authors declare no conflict of interest. biogenesis of lysosome-related organelles complex 1 (BLOC-1) This article is a PNAS Direct Submission. (7). Despite some controversial results, the association between 1To whom correspondence should be addressed. E-mail: [email protected]. multiple variants in DTNBP1 and schizophrenia has been repli- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. cated by several independent studies (8, 9). Furthermore, reduced 1073/pnas.1114569108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1114569108 PNAS | November 15, 2011 | vol. 108 | no. 46 | 18831–18836 Downloaded by guest on September 23, 2021 Tissue-Specific Regulation of Changes in Neurotransmitter Systems. While determining the genetic specificity of the observed phe- notypes, we discovered tissue-specific functions of Ddysb using the Gal4/Upstream Activation System (Gal4/UAS) binary system (22). Ddysb RNAi (DdysbIR) and UAS-Ddysb flies were used for Ddysb knockdown and overexpression (Fig. S2). At the NMJ, we first determined whether glutamatergic transmission was sup- ported by a presynaptic or postsynaptic function of Ddysb. Transgenic RNAi was targeted to either presynaptic neurons or postsynaptic muscle cells. We found that silencing Ddysb func- tions pan-neuronally [embryonic lethal abnormal vision (elav)- Gal4/Y;DdysbIR-1/+], instead of in the muscle cells (DdysbIR-1/+; muscle Gal4 (C57)/+), caused a similarly reduced EJC amplitude in the dysb1 mutant (Fig. 2A). To confirm further the presynaptic role of Ddysb, we performed a rescuing experiment, showing that pan-neuronal expression of the UAS-Ddysb transgene in the dysb1 mutant background (elav-Gal4/Y;UAS-Ddysb/+;dysb1) success- fully restored the EJC to the WT level (Fig. 2B). Moreover, pan- neuronal overexpression of Ddysb by two copies in the WT background (elav-Gal4;UAS-Ddysb) led to increased EJC ampli- tude (Fig. S3A). Thus, Ddysb regulates the glutamatergic synaptic transmission presynaptically in a dosage-dependent manner. Unexpectedly, the neuronal expression of Ddysb in dysb1 mu- + 1 1 tant (UAS-Ddysb/ ;elav-Gal4(III) dysb /dysb ) did not rescue the dopamine level in the adult head (Fig. 2C, Left). This result prompted us to test the possibility that Ddysb might have non- neuronal functions. We found that expression of Ddysb with a glia- + Fig. 1. Characterization of the Ddysb mutant. (A) Transposon insertion site. specific driver, Reversed polarity (Repo)-Gal4 (UAS-Ddysb/ ; (B) Representative Western blots and group data showing reduced expres- Repo-Gal4 dysb1/dysb1) suppressed the elevated dopamine level in sion of Ddysb in the head of the dysb1 mutant (t test; P = 0.007; n = 5). (C) the dysb1 mutant (Fig. 2C, Right). Therefore, Ddysb appears to The dysb1 mutant shows decreased EJC amplitude (t test; P = 0.002, 0.02, regulate glutamatergic transmission and dopamine level through 0.03, and 2.1E-6 for calcium concentrations of 0.15, 0.2, 0.3,
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