Functional Study Of Schizophrenia Susceptibility Gene DTNBP1in Drosophila

The imbalance of multiple neurotransmitter systems is a strikingpathophysiological feature of many mental disorders, schizophrenia in particular. Ithas been a challenge in delineating underlying mechanisms of how the geneticsusceptibility of schizophrenia confers to its pathophysiological and clinicalmanifestations.In the current study, we began our inquiry from the analysis of a Drosophilamutant, dysb1, in the homolog of schizophrenia susceptibility gene DTNBP1(Ddysb). We found that the reduced expression of Ddysb in dysb1mutant lead toboth defected glutamatergic transmission and elevated dopamine level as well as aserial of behavioral abnormalities including memory deficits, hyperactivity, andmating disorientation. Although widely distributed in Drosophila brain, onlyDdysb’s function in neurons is related to the glutamatergic transmission and memoryperformance, and only its function in glial cells plays a role in regulating theindividual development, brain dopamine level, locomotor activity, and matingorientation. This observation suggests the independent functions of Ddysb inneurons versus glia. Further pharmacological and genetic evidence revealed that thehypoglutamatergia in dysb1mutant is responsible for its memory impairment, andthe hyperdopaminergia leads to abnormal locomotion and altered mating orientation.In search of how Ddysb regulates dopamine level in glial cells, we found that aglia-specific N-β-alanyl-biogenic amine synthetase, ebony, is decreasedsignificantly in both the mRNA and the protein level. A positive correlation betweenthe expression of Ddysb and Ebony was also disclosed in further studies. Thus,Ddysb regulates glutamatergic transmission through its neuronal function anddopamine metabolism through regulation of Ebony expression in glial cells.Although Ddysb is essential for the individual development, acute induction ofDdysb transgene rescued the phenotypes in the dysb1mutant, suggesting that Ddysbplays an acute physiological role in regulating neurotransmitters and behaviors. Inaddition, all the phenotypes in dysb1mutant were rescued by expression of humanDTNBP1transgene, indicating that there exists substantial conservation between human DTNBP1and Ddysb. Furthermore, our preliminary data showed that Ddysbinteracted with another schizophrenia susceptibility gene DISC1on the participationof glutamatergic transmission and reversal learning, which expands our research onthe genetic network of Ddysb.