Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model

BackgroundAutism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines—signaling molecules made in mitochondria—that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders. Objectives and MethodsWe used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice. ResultsWe found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities. ConclusionsHyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development.背景：自闭症谱系障碍（Autism spectrum disorders, ASDs）由遗传与环境因素共同诱发。线粒体可通过感知细胞及其所处环境的化学变化，调控基因编码的代谢网络，从而实现基因与环境的关联。线粒体ATP及其他代谢物属于丝裂原（mitokines）——一类由线粒体合成的信号分子，它们经调控后从细胞释放，通过嘌呤能信号通路（purinergic signaling）向邻近细胞传递细胞健康与危险状态的信号。目前学界尚未在自闭症谱系障碍中探索嘌呤能信号通路的作用。 研究目标与方法：本研究采用孕鼠暴露于聚肌胞苷酸（poly(IC)）的母体免疫激活（maternal immune activation, MIA）小鼠模型，并辅以非选择性嘌呤能拮抗剂苏拉明（suramin）处理，以探究嘌呤能信号通路在C57BL/6J小鼠中的功能。 研究结果：本研究发现，抗嘌呤能疗法（antipurinergic therapy, APT）可纠正该模型中构成自闭症样表型的16种多系统异常，具体包括：核心社交缺陷与感觉运动协调异常的改善、小脑浦肯野细胞（Purkinje cell）丢失的预防、超微结构层面突触形态异常的矫正，以及体温过低、代谢异常、线粒体功能异常、P2Y2与P2X7嘌呤能受体表达异常，还有ERK1/2与CAMKII信号转导异常的纠正。 结论：高嘌呤能信号（hyperpurinergia）是自闭症谱系障碍聚肌胞苷酸小鼠模型多系统异常的核心且可干预特征。抗嘌呤能疗法为完善自闭症及相关谱系障碍的现有发病机制认知提供了全新工具，同时也为新药研发开辟了崭新路径。