Recovery of the synaptic transmission genomic fabrics in the hypothalamic paraventricular nucleus of a rat model of autism treated with PMX53

We profiled the whole transcriptomes of male and female rat hypothalamic paraventricular nuclei to determine the remodeling of the genomic fabrics responsible for the glutamatergic, GABAergic, dopaminergic, cholinergic and serotonergic transmission in epilepsy and recovery following treatment with PMX53. The rats were prenatally exposed (G15) to betamethasone followed by repeated adiministration of N-Methyl-D-Aspartic acid (NMDA) on postnatal days 12, 13 and 15 which triggered infantile spasms and autistic behavior. Pups were treated with PMX53 (a potent C5ar1 antagonist) on days 13, 14 and 15 prior to NMDA administration to determine what effects the treatment had on transcriptome recovery. Our Genomic Fabric Paradigm (GFP) is proposed as a transformative research approach to enhance the understanding of the brain transcriptomic alterations in epileptic rats and recovery following various treatments. The genomic fabric of a particular synapse is the structured transcriptome associated with the most interconnected and stably expressed gene network responsible for that type of neurotransmission. GFP refines the description of functional pathways by selecting the most prominent genes and determining their networking. Moreover, it quantifies the remodeling of functional pathways and their interplay in disease and recovery in response to a treatment. We found that priming with betamethasone had substantial consequences on the topology of the genomic fabrics of all kind of synaptic transmission, that NMDA-induced spasms strongly exacerbated the remodeling of these fabrics and that PMX53 treatment recovered partially the the normal synaptic transcriptomes.我们对雌性与雄性大鼠的下丘脑室旁核（hypothalamic paraventricular nuclei）全转录组进行了谱分析，旨在明确癫痫状态下以及经PMX53治疗后恢复过程中，介导谷氨酸能、γ-氨基丁酸能、多巴胺能、胆碱能及5-羟色胺能神经传递的基因组结构（genomic fabrics）的重塑特征。实验大鼠于妊娠第15天（G15）暴露于倍他米松，随后在出生后第12、13、15天反复给予N-甲基-D-天冬氨酸（N-Methyl-D-Aspartic acid, NMDA），以诱导婴儿痉挛症与自闭症样行为。幼鼠在NMDA给药前的第13、14、15天接受PMX53（一种强效C5ar1拮抗剂）处理，以明确该治疗对转录组恢复的调控效应。我们提出的基因组结构范式（Genomic Fabric Paradigm, GFP）可作为一种变革性研究方法，以加深对癫痫大鼠脑转录组改变及各类治疗后恢复过程的理解。特定突触的基因组结构，是与介导该类型神经传递的关联最紧密且表达最稳定的基因网络相关的结构化转录组。该范式通过筛选核心基因并解析其调控网络，优化了功能通路的描述；此外，它可量化疾病状态下功能通路的重塑情况，以及治疗响应过程中各通路间的相互作用。我们发现，倍他米松预处理对各类突触传递的基因组结构拓扑特征具有显著影响，NMDA诱导的痉挛强烈加剧了这些结构的重塑，而PMX53治疗可部分恢复正常的突触转录组。