Adenosine and schizophrenia: mechanisms and therapies

描述（由申请人提供）：本延续申请继续阐述“精神分裂症的腺苷假说”，该假说预测大脑中腺苷（ADO）稳态的破坏会产生模仿特定精神分裂症（SZ）症状的行为效应。从我们以前的资助期间的研究表明，ADO稳态在成人大脑中的破坏影响多个脑回路牵连的SZ的病理生理。重要的是，我们提供了ADO强化治疗的抗精神病潜力的证据。我们的更新申请将评估ADO稳态发育功能障碍对小鼠SZ相关症状发生的贡献。我们提出的工作基于以下基本原理：（i）ADO调节在大脑发育中起着关键作用。(ii)的 胎盘的ADO屏障在分离母体和胎儿的ADO系统中起关键作用。(iii)产前免疫刺激是SZ的一个环境危险因素，对发育中的ADO稳态提出了挑战。(iv)成人脑中的ADO稳态受星形胶质细胞控制;因此星形胶质细胞生理学的损伤将影响ADO稳态。(v)我们上一个资助期的数据表明，治疗性ADO增强具有抗SZ潜力。在这里，我们将解决的核心假设，发育功能障碍的腺苷稳态有助于精神分裂症的病理生理学，腺苷为基础的干预措施提供了新的机会，治疗干预。使用一组新的转基因小鼠，其具有影响胎儿脑发育期间ADO稳态的条件突变，SZ小鼠妊娠感染模型中母体/胎儿界面处基于ADO的治疗操作，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测定，我们将在三个特定目标中解决我们的假设：（1）检验胎儿破坏ADO稳态影响脑发育的假设。(2)检验ADO稳态失调导致SZ妊娠感染模型中涉及的神经发育脱轨的假设。(3)检验出生后ADO增强干预可以预防或抑制产前免疫激发后代中SZ相关症状的预测。意义和影响：拟议的项目将确定胎儿脑发育过程中特定的腺苷能功能障碍作为SZ发展的可能促发因素的作用。重要的是，我们的研究将测试在母体/胎儿界面直接干扰ADO信号传导的预防性治疗措施。此外，我们的研究结果将解决ADO，大脑发育，神经胶质细胞和SZ之间的潜在联系的知识的关键差距-一个研究不足的研究领域。通过确定恢复青少年和成年期脑功能的星形胶质细胞依赖的ADO稳态控制的治疗潜力，我们的研究将为青少年和成年期脑功能的恢复确定一种新的治疗原则。 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.