Remodeling of synaptic transmission genomic fabrics in the hypothalamic paraventricular nucleus of a rat model of autism

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 autism. The rats were prenatally exposed (G15) to betamethasone followed by repeated adiministration of N-Methyl-D-Aspartic acid on postnatal days 12, 13 and 15 which triggered the infantile spasms and autism spectrum disease behavior. Pups were treated with saline on days 13, 14 and 15 prior to NMDA administration. Our Genomic Fabric Paradigm (GFP) is proposed as a transformative research approach to enhance the understanding of the brain transcriptomic alterations in autistic rats . 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 and that NMDA-induced spasms strongly exacerbated the remodeling of these fabrics.本研究对雌雄大鼠下丘脑室旁核（hypothalamic paraventricular nuclei）的全转录组（transcriptome）进行了全景式分析，旨在明确自闭症中介导谷氨酸能（glutamatergic）、γ-氨基丁酸能（GABAergic）、多巴胺能（dopaminergic）、胆碱能（cholinergic）及5-羟色胺能（serotonergic）神经传递的基因组结构（genomic fabrics）重塑特征。实验大鼠于孕第15天（G15）暴露于倍他米松（betamethasone），随后分别于出生后第12、13、15天反复给予N-甲基-D-天冬氨酸（N-Methyl-D-Aspartic acid，NMDA），成功诱导出幼鼠痉挛症与自闭症谱系障碍样行为；对照组幼鼠则于NMDA给药前的第13、14、15天给予生理盐水处理。本研究提出基因组结构范式（Genomic Fabric Paradigm，GFP）作为一种变革性研究手段，以深化对自闭症模型大鼠脑内转录组改变的认知。特定突触（synapse）的基因组结构，指的是与介导该类型神经传递的、连接最紧密且表达最稳定的基因网络相关联的结构化转录组。GFP通过筛选核心基因并解析其互作网络，优化了功能通路的描述范式；此外，该方法还可量化功能通路的重塑过程，以及其在疾病进程与治疗应答恢复过程中的互作模式。研究结果表明，倍他米松预处理对各类突触传递的基因组结构拓扑特征均产生了显著影响，而NMDA诱导的痉挛症则进一步大幅加剧了这些结构的重塑程度。