Strekalova Tatyana, Svirin Evgeniy, Veniaminova Ekaterina, Kopeikina Ekaterina, Veremeyko Tatyana, Yung Amanda W Y, Proshin Andrey, Walitza Susanne, Anthony Daniel C, Lim Lee Wei, Lesch Klaus-Peter, Ponomarev Eugene D
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, the Netherlands.
Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, Moscow, Russia.
Brain Behav Immun Health. 2021 Jul 27;16:100306. doi: 10.1016/j.bbih.2021.100306. eCollection 2021 Oct.
Gangliosides are glycosphingolipids, which are abundant in brain, are known to modulate ion channels and cell-to-cell communication. Deficiencies can result in aberrant myelination and altered immune responses, which can give rise to neurodevelopmental psychiatric disorders. However, to date, little mechanistic data is available on how ganglioside deficiencies contribute to the behavioural disorders. In humans, the loss of lactosylceramide-alpha-2,3-sialyltransferase (ST3Gal5) leads to a severe neuropathology, but in ST3Gal5 knock-out () mice the absence of GM3 and associated a-, b- and c-series gangliosides is partially compensated by 0-series gangliosides and there is no overt behavioural phenotype. Here, we sought to examine the behavioural and molecular consequences of GM3 loss more closely. Mutants of both sexes exhibited impaired conditioned taste aversion in an inhibitory learning task and anxiety-like behaviours in the open field, moderate motor deficits, abnormal social interactions, excessive grooming and rearing behaviours. Taken together, the aberrant behaviours are suggestive of an autism spectrum disorder (ASD)-like syndrome. Molecular analysis showed decreased gene and protein expression of proteolipid protein-1 () and over expression of proinflammatory cytokines, which has been associated with ASD-like syndromes. The inflammatory and behavioural responses to lipopolysaccharide (LPS) were also altered in the mice compared to wild-type, which is indicative of the importance of GM3 gangliosides in regulating immune responses. Together, the mice display ASD-like behavioural features, altered response to systemic inflammation, signs of hypomyelination and neuroinflammation, which suggests that deficiency in a- and b-series gangliosides could contribute to the development of an ASD-like pathology in humans.
神经节苷脂是糖鞘脂类，在大脑中含量丰富，已知其可调节离子通道和细胞间通讯。其缺乏会导致异常髓鞘形成和免疫反应改变，进而引发神经发育性精神障碍。然而，迄今为止，关于神经节苷脂缺乏如何导致行为障碍的机制数据很少。在人类中，乳糖基神经酰胺-α-2,3-唾液酸转移酶（ST3Gal5）的缺失会导致严重的神经病理学改变，但在ST3Gal5基因敲除小鼠中，GM3以及相关的a、b和c系列神经节苷脂的缺失部分由0系列神经节苷脂补偿，且没有明显的行为表型。在此，我们试图更深入地研究GM3缺失的行为和分子后果。两种性别的突变体在抑制性学习任务中表现出条件性味觉厌恶受损，在旷场实验中表现出焦虑样行为，有中度运动缺陷、异常社交互动、过度梳理毛发和竖毛行为。综合来看，这些异常行为提示可能存在类似自闭症谱系障碍（ASD）的综合征。分子分析显示，蛋白脂蛋白-1（PLP1）的基因和蛋白表达降低，促炎细胞因子表达上调，这与类似ASD的综合征有关。与野生型相比，GM3基因敲除小鼠对脂多糖（LPS）的炎症和行为反应也发生了改变，这表明GM3神经节苷脂在调节免疫反应中具有重要作用。总之，GM3基因敲除小鼠表现出类似ASD的行为特征、对全身炎症反应的改变、髓鞘形成不足和神经炎症的迹象，这表明a和b系列神经节苷脂的缺乏可能导致人类出现类似ASD的病理状况。
