Mutations in the dystrobrevin binding protein 1 (DTNBP1) gene that encodes for the dysbindin-1 protein, are associated with a higher risk for schizophrenia. Interestingly, individuals carrying high-risk alleles in this gene have been associated with an increased incidence of negative symptoms for the disease, which include anhedonia, avolition and social withdrawal. Here we evaluated behavioral and neurochemical changes in a hypomorphic Drosophila mutant for the orthologue of human Dysbindin-1, dysb¹.

Mutant dysb¹ flies exhibit altered social space parameters, suggesting asocial behavior, accompanied by reduced olfactory performance. Moreover, dysb¹ mutant flies show poor performance in basal and startle-induced locomotor activity. We also report a reduction in serotonin brain levels and changes in the expression of the Drosophila serotonin transporter (dSERT) in dysb¹ flies. Our data show that the serotonin-releasing amphetamine derivative 4-methylthioamphetamine (4-MTA) modulates social spacing and locomotion in control flies, suggesting that serotonergic circuits modulate these behaviors. 4-MTA was unable to modify the behavioral deficiencies in mutant flies, which is consistent with the idea that the efficiency of pharmacological agents acting at dSERT depends on functional serotonergic circuits.

Thus, our data show that the dysb¹ mutant exhibits behavioral deficits that mirror some aspects of the endophenotypes associated with the negative symptoms of schizophrenia. We argue that at least part of the behavioral aspects associated with these symptoms could be explained by a serotonergic deficit. The dysb¹ mutant presents an opportunity to study the molecular underpinnings of schizophrenia negative symptoms and reveals new potential targets for treatment of the disease.

编码dysbindin-1 蛋白的dystrobrevin 结合蛋白1 ( DTNBP1 ) 基因的突变与更高的精神分裂症风险相关。有趣的是，在该基因中携带高风险等位基因的个体与该疾病阴性症状的发生率增加有关，包括快感缺乏、意志消沉和社交退缩。在这里，我们评估了人类Dysbindin-1、dysb ¹直向同源物的亚形果蝇突变体的行为和神经化学变化。

突变的dysb ¹苍蝇表现出改变的社会空间参数，表明非社会行为，伴随着嗅觉性能的降低。此外，dysb ¹突变果蝇在基础和惊吓诱导的运动活动中表现不佳。我们还报告了dysb ¹中5-羟色胺脑水平的降低和果蝇5-羟色胺转运蛋白（dSERT）表达的变化苍蝇。我们的数据显示释放血清素的苯丙胺衍生物 4-甲基硫代苯丙胺 (4-MTA) 调节对照果蝇的社交间隔和运动，表明血清素能回路调节这些行为。4-MTA 无法改变突变果蝇的行为缺陷，这与药物作用于 dSERT 的效率取决于功能性血清素能回路的想法一致。

因此，我们的数据显示，dysb ¹突变体表现出行为缺陷，反映了与精神分裂症阴性症状相关的内表型的某些方面。我们认为，至少部分与这些症状相关的行为方面可以用血清素缺乏来解释。该dysb ¹突变体的礼物来研究精神分裂症阴性症状的分子基础的机会，并揭示了新的潜在靶点治疗疾病。