Antipsychotic medications are inefficient at treating symptoms of schizophrenia (SCZ), and N-methyl d-aspartate receptor (NMDAR) agonists are potential therapeutic alternatives. As such, these agonists may act on different pathways and proteins altered in the brains of patients with SCZ than do antipsychotic medications. Here, we investigate the effects of administration of the antipsychotic haloperidol and NMDAR agonist d-serine on function and expression of three proteins that play significant roles in SCZ: nitric oxide synthase 1 adaptor protein (NOS1AP), dopamine D2 (D2) receptor, and disrupted in schizophrenia 1 (DISC1). We administered haloperidol or d-serine to male and female Sprague Dawley rats via intraperitoneal injection for 12 days and subsequently examined cortical expression of NOS1AP, D2 receptor, and DISC1. We found sex-specific effects of haloperidol and d-serine treatment on the expression of these proteins. Haloperidol significantly reduced expression of D2 receptor in male, but not female, rats. Conversely, d-serine reduced expression of NOS1AP in male rats and did not affect D2 receptor expression. d-serine treatment also reduced expression of DISC1 in male rats and increased DISC1 expression in female rats. As NOS1AP is overexpressed in the cortex of patients with SCZ and negatively regulates NMDAR signaling, we subsequently examined whether treatment with antipsychotics or NMDAR agonists can reverse the detrimental effects of NOS1AP overexpression in vitro as previously reported by our group. NOS1AP overexpression promotes reduced dendrite branching in vitro, and as such, we treated cortical neurons overexpressing NOS1AP with different antipsychotics (haloperidol, clozapine, fluphenazine) or d-serine for 24 h and determined the effects of these drugs on NOS1AP expression and dendrite branching. While antipsychotics did not affect NOS1AP protein expression or dendrite branching in vitro, d-serine reduced NOS1AP expression and rescued NOS1AP-mediated reductions in dendrite branching. Taken together, our data suggest that d-serine influences the function and expression of NOS1AP, D2 receptor, and DISC1 in a sex-specific manner and reverses the effects of NOS1AP overexpression on dendrite morphology.

抗精神病药在治疗精神分裂症（SCZ）症状方面效率低下，N-甲基d-天冬氨酸受体（NMDAR）激动剂是潜在的治疗选择。因此，与抗精神病药物相比，这些激动剂可能作用于SCZ患者大脑中的不同途径和蛋白质发生改变。在这里，我们研究了抗精神病药物氟哌啶醇和NMDAR激动剂d-丝氨酸对SCZ中起重要作用的三种蛋白的功能和表达的影响：一氧化氮合酶1衔接蛋白（NOS1AP），多巴胺D2（D2）受体和精神分裂症1（DISC1）中断。我们通过以下方式对雄性和雌性Sprague Dawley大鼠施用了氟哌啶醇或d-丝氨酸腹腔注射12天，随后检查NOS1AP，D2受体和DISC1的皮质表达。我们发现氟哌啶醇和d-丝氨酸处理对这些蛋白的表达具有性别特异性。氟哌啶醇显着降低雄性大鼠但非雌性大鼠中D2受体的表达。相反，d-丝氨酸降低了雄性大鼠中NOS1AP的表达，并且不影响D2受体的表达。d-丝氨酸处理还降低了雄性大鼠中DISC1的表达，并提高了雌性大鼠中DISC1的表达。由于NOS1AP在SCZ患者皮层中过表达并且对NMDAR信号负调节，因此我们随后检查了抗精神病药或NMDAR激动剂的治疗是否可以逆转NOS1AP在体外的过度表达所产生的有害影响，正如我们小组先前报道的那样。NOS1AP过表达促进体外树枝状分支减少，因此，我们用不同的抗精神病药（氟哌啶醇，氯氮平，氟奋乃静）或d治疗过表达NOS1AP的皮质神经元-丝氨酸24小时，并确定这些药物对NOS1AP表达和树枝状分支的影响。虽然抗精神病药在体外不影响NOS1AP蛋白表达或树枝状分支，但d-丝氨酸可降低NOS1AP表达并挽救NOS1AP介导的树枝状分支减少。两者合计，我们的数据表明d-丝氨酸以性别特异性方式影响NOS1AP，D2受体和DISC1的功能和表达，并逆转NOS1AP过表达对枝晶形态的影响。