ASD-like behaviors, a dysregulated inflammatory response and decreased expression of PLP1 characterize mice deficient for sialyltransferase ST3GAL5

Abstract

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 ( St3gal5−/− ) 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 ( Plp1 ) 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 St3gal5−/− mice compared to wild-type, which is indicative of the importance of GM3 gangliosides in regulating immune responses. Together, the St3gal5−/− 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.

Excessive aggression, ADHD- and ASD-like phenotypes in TPH2- and brain ganglioside-deficient mice

“…While molecular changes reported here are based on gene expression data, they are likely to also result in the changes in the level of protein expression. Similar studies reporting stress-induced increases of aggressive behavior in mice killed on the next day after the last manipulation showed congruent changes on gene and protein levels for the markers investigated here [32], and for myelin proteins [68].…”

Immunomodulatory effects of new phytotherapy on human macrophages and TLR4- and TLR7/8-mediated viral-like inflammation in mice

“…The magnitude of the systemic inflammatory response was evaluated by measuring the relative expression of pro-inflammatory genes in the liver and spleen ( 22 , 51 , 52 ). In both organs, the resiquimod challenge induced a significant increase in SAA-2, ACE-2, CXCL1, and CXCL10.…”

Aberrant Ganglioside Functions to Underpin Dysregulated Myelination, Insulin Signalling, and Cytokine Expression: Is There a Link and a Room for Therapy?

“…Recently, we studied the baseline behaviour of St3gal5 −/− mice, as data in the available literature was scarce [ 56 ]. We have found substantial increases in dominant and neutral social behaviours in male mutants and decreased neutral sociability of female St3gal5 −/− mice, as well as other behavioural alterations resembling ASD-like and ASD-accompanying features, i.e., repetitive grooming behaviour and increased anxiety.…”

“…We demonstrated profound sex differences in the behavioural reaction to LPS administration. While systemic inflammation led to a substantial increase in dominant and aggressive behaviours in St3gal5 −/− males, in female mice, an increase in those behaviours was observed in wild-type control mice [ 56 ]. Sex differences were also found in the cytokine expression response to LPS administration.…”