Adenosine and schizophrenia: mechanisms and therapies

描述(由申请人提供)：这一续订申请继续解决‘精神分裂症的腺苷假说’，该假说预测大脑中腺苷(ADO)稳态的破坏会产生类似于特定精神分裂症(SZ)症状的行为效应。我们之前资助时期的研究表明，成人大脑中ADO动态平衡的破坏影响到与SZ的病理生理学有关的多个大脑回路。重要的是，我们为ADO增强疗法的抗精神病潜力提供了证据。我们的更新应用将评估ADO动态平衡的发育障碍在小鼠SZ相关症状发生中的作用。我们提出的工作基于以下基本原理：(I)ADO调节在大脑发育中发挥关键作用。(Ii) 胎盘ADO屏障在母体和胎儿ADO系统的分离中起着关键作用。(Iii)产前免疫刺激是SZ的一个环境风险因素，对发育中的ADO动态平衡构成挑战。(4)成人脑内ADO动态平衡受星形胶质细胞控制，星形胶质细胞生理功能受损会影响ADO动态平衡。(V)我们上一个资助期的数据显示，治疗性ADO增强具有抗SZ的潜力。在这里，我们将讨论一个中心假设，即腺苷稳态的发育障碍有助于精神分裂症的病理生理学；基于腺苷的干预为治疗干预提供了新的机会。通过使用一组在胎儿大脑发育期间具有影响ADO稳态的条件突变的新型转基因小鼠，在SZ小鼠妊娠感染模型中基于ADO的母胎界面的治疗操作，在青春期和成年期基于ADO的治疗干预，以及对选定的SZ相关行为特征征税的行为分析，我们将在三个具体目标上解决我们的假设：(1)测试胎儿ADO稳态破坏会影响大脑发育的假设。(2)验证ADO稳态失调导致SZ妊娠感染模型中神经发育脱轨的假说。(3)检验出生后加强ADO干预可以预防或抑制因产前免疫挑战而产生的后代出现SZ相关症状的预测。意义和影响：拟议的项目将确定特定的腺苷能功能障碍在胎儿大脑发育中的作用(S)，作为可能的诱发因素，导致深圳特区的发展。重要的是，我们的研究将测试在母体/胎儿界面直接干扰ADO信号的预防性治疗措施。此外，我们的发现将解决有关ADO、脑发育、神经胶质细胞和SZ之间潜在联系的知识差距--这是一个研究很少的研究领域。通过确定在青春期和成年期恢复基于星形胶质细胞的ADO依赖的动态平衡控制大脑功能的治疗潜力，我们的研究将定义一种新的治疗原则 SZ的防治。

DESCRIPTION (provided by applicant): This renewal application continues to address the 'adenosine hypothesis of schizophrenia', which predicts that disruption of adenosine (ADO) homeostasis in the brain produces behavioral effects mimicking specific schizophrenia (SZ) symptoms. Studies from our previous funding period demonstrated that disruption of ADO homeostasis in the adult brain affected multiple brain circuits implicated in the pathophysiology of SZ. Importantly, we provided evidence for the antipsychotic potential of ADO augmentation therapy. Our renewal application will assess the contribution of developmental dysfunction of ADO homeostasis to the genesis of SZ-related symptoms in mice. Our proposed work is based on the following rationale: (i) ADO regulation plays a critical role in brain development. (ii) The placental ADO-barrier plays a key role in separating the maternal from the fetal ADO-system. (iii) Prenatal immune stimulation, an environmental risk factor for SZ, challenges developmental ADO homeostasis. (iv) ADO homeostasis in the adult brain is under the control of astrocytes; therefore impairment of astrocyte physiology will affect ADO homeostasis. (v) Data from our previous funding period demonstrated an anti-SZ potential of therapeutic ADO augmentation. Here, we will address the CENTRAL HYPOTHESIS that developmental dysfunction of adenosine homeostasis contributes to the pathophysiology of schizophrenia; and that adenosine-based interventions provide new opportunities for therapeutic interventions. Using a novel set of transgenic mice with conditional mutations affecting ADO-homeostasis during fetal brain development, ADO-based therapeutic manipulations at the maternal/fetal interface in the mouse gestational infection model of SZ, ADO-based therapeutic interventions during adolescence and adulthood, and behavioral assays to tax selected SZ-related behavioral traits, we will address our hypothesis in three Specific Aims: (1) Test the hypothesis that fetal disruption of ADO homeostasis affects brain development. (2) Test the hypothesis that dysregulation of ADO homeostasis contributes to the neurodevelopmental derailments implicated in the gestational infection model of SZ. (3) Test the prediction that postnatal ADO augmenting interventions can prevent or suppress SZ-related symptoms in offspring derived from a prenatal immune challenge. Significance and Impact: The proposed project will define the role(s) of specific adenosinergic dysfunctions during fetal brain development as possible precipitating factor for the development of SZ. Importantly, our research will test preventative therapeutic measures directly interfering with ADO signaling at the maternal/fetal inter- face. In addition our findings will address a critical gap in knowledge about the potential link between ADO, brain development, glia, and SZ - a much understudied research field. By identifying the therapeutic potential of restoring astrocyte-based ADO-dependent homeostatic control of brain functions in adolescence and adult- hood, our studies will define a novel therapeutic principle for the prevention and treatment of SZ.