Transcriptome of the audiogenic rat strain and identification of possible audiogenic epilepsy-associated genes

Audiogenic epilepsy (AE), developing in rodent strains in response to loud sound, is widely used as the model of generalized convulsive epilepsy. The molecular and genetic mechanisms that determine the expression of AE are currently non well understood. In the present work we compared transcriptomes from the inferior and superior colliculi (corpora quadrigemina), the crucial epileptogenic midbrain zone for AE in order to identify genes associated to the AE phenotype. Transcriptomes of rats from three strains were compared: Krushinsky-Molodkina (KM) strain (100% AE-prone); Wistar outbred rats (with no AE proneness) and "0" strain, selected from F2 KMxWistar hybrids for the lack of AE. It is shown that KM strain gene expression profile have a number of characteristic differences from those of Wistar and "0" strains. In particular, KM has increased expression of a number of genes involved in positive regulation of the MAPK signaling cascade, as well as genes, responsible for positive regulation of apoptotic processes. The next characteristic difference between the KM strain from Wistar and "0" is a multiple increase in the expression level of the Ttr gene, which is known to be associated with family amyloid polyneuropathy in humans. Further, the KM strain showed a significant decrease in the expression of the Msh3 gene involved in the DNA mismatch repair system, Acsm5, coding a mitochondrial acyl-CoA synthetase specific for medium chain family member 5, and in a number of genes of the oxidative phosphorylation system, and a number of some other genes. Our data confirm the complex multigenic nature of AE inheritance in rodents. A comparison with the data obtained from other AE rodent strains suggests that the convulsive phenotype could develop differently in audiogenic rat strains selected independently. Although, the finding of parallel differences in certain genes expression in AE-prone hamsters (another rodent species) indicate the common (and crucial) neurogenetic defects, leading to AE phenotype in rodents in general.声源性癫痫（Audiogenic epilepsy, AE）在啮齿类品系中由强声刺激诱发，被广泛用作全面性惊厥性癫痫的动物模型。目前，决定AE表型表达的分子与遗传机制尚未完全阐明。本研究针对AE关键的致痫中脑区域——下丘与上丘（四叠体）——的转录组进行比较分析，以期鉴定与AE表型相关的基因。本次研究对比了三个品系大鼠的转录组：克鲁申斯基-莫洛德金娜（Krushinsky-Molodkina, KM）品系（100%易患AE）、Wistar远交群大鼠（无AE易感性），以及从F2代KM×Wistar杂交后代中筛选获得的"0"品系（无AE易感性）。研究结果显示，KM品系的基因表达谱与Wistar及"0"品系存在多处特征性差异。具体而言，KM品系中参与MAPK信号级联正向调控的多个基因，以及调控细胞凋亡过程的相关基因表达水平上调。另一项显著特征性差异为，KM品系中Ttr基因的表达水平显著升高，该基因已知与人类家族性淀粉样多神经病相关。此外，KM品系中参与DNA错配修复系统的Msh3基因、编码特异性针对中链家族成员5的线粒体酰基辅酶A合成酶的Acsm5基因，以及氧化磷酸化系统的多个基因与其他部分基因的表达均显著下调。本研究数据证实了啮齿类动物AE遗传的复杂多基因特性。通过与其他AE啮齿类品系的研究数据进行对比，结果提示独立选育的声源性癫痫大鼠品系，其惊厥表型的发生机制可能存在差异。不过，在另一种啮齿类——仓鼠——的AE易患品系中也观察到部分基因表达的平行差异，这表明存在普遍且关键的神经遗传缺陷，总体上可导致啮齿类动物出现AE表型。