Evgeniy Svirin1,2*, Ekaterina Veniaminova2*, Ekaterina Kopeikina3*, Tatyana Veremeyko3, Amanda W.Y. Yung3, Shawn Zheng Kai Tan4, Sharafuddin Khairuddin4, Lee Wei Lim4, Eugene D. Ponomarev3#, Tatyana Strekalova1,2,5#. Klaus-Peter Lesch1,2,5#
1 Maastricht University, Maastricht, The Netherlands,
2 Sechenov First Moscow State Medical University, Moscow, Russia,
3 The Chinese University of Hong Kong, Hong Kong,
4 Hong Kong University, Hong Kong,
5 University of Würzburg, Würzburg, Germany.
*,# - equal contribution.
GM3-synthase (ST3GAL5) is an enzyme synthesizing major brain gangliosides. In humans, genetic aberrations in this gene lead to a higher incidence of neurodevelopmental diseases, and in some cases, to a severe neuropsychiatric phenotype. There is evidence of an involvement of gangliosides in the regulation of insulin receptor (IR) function. IR isoforms IRA and IRB are abundant in the CNS, where IRA is restricted to neurons, while glia expresses both IRA and IRB. IRs are involved in broad spectrum of functions in the CNS, and in neuroinflammation. In the periphery, gangliosides regulate glucose metabolism, and play role in the pathogenesis of type-2 diabetes, a condition linked to increased mortality in COVID-19 patients. Moreover, gangliosides play a crucial role in myelination.
We tested motor function and locomotion, emotional, social, and exploratory behavior. We investigated expression of the IR subtypes IRA and IRB in the brain cortex and the spleen and metabolic regulation in the glucose tolerance test in adult St3gal5−/−mice. Expression of pro-inflammatory cytokines Il-1β, Il-6, and TNF, was assessed in cerebral cortex and spleen. Also, in cerebral cortex, we measured the expression of four major myelination-related proteins Mbp, Plp1, and Mag.
Motor deficits and increased anxiety-like behavior, lowered exploratory behavior, and impaired conditioned taste aversion were evident in St3gal5−/− mice of both sexes. Hyperlocomotion, and increased parameters of neutral social interaction and dominant behavior were observed in St3gal5−/− male mice. In both sexes, we found elevated expression of Il-1β in both the cerebral cortex and spleen. Finally, we demonstrated sex-independent downregulation of the Plp1 gene and protein expression in the cortex. Thus, the genetic deficiency of St3gal5 resulted in sex-dependent changes in the expression of IR subtypes in spleen, but not in the cortex, which may suggest altered glucose metabolism in the periphery.
St3gal5−/− mice demonstrated neurobiological abnormalities that are reminiscent to the endophenotypes of developmental neuropsychiatric disorders Our findings underpin the possible role of major brain gangliosides in the neurodevelopmental disorder-associated behaviors.