The impact of ST3GAL5 deficiency, the key enzyme in brain-specific ganglioside synthesis, on behaviour, metabolic regulation and neuroinflammation: a study in a new mouse model

Abstract

The lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5) is a key enzyme in the biosynthesis of brain-specific gangliosides which are critical in many CNS functions. Genetic aberrations of ST3GAL5 in humans are associated with intellectual disability, epilepsy, blindness, deafness, mental retardation, metabolic syndrome and altered neuroinflammation.

Aims:

Here, we studied the impact of genetic ST3GAL5 deficiency on motor, emotional and cognitive behaviour, metabolic regulation and neuroinflammation using a newly generated a mouse model lacking the ST3GAL5 gene (ST3ko).

Methods:

Young male and female ST3ko mice and wild type littermates were subjected to previously validated battery of behavioural tests for motor, emotional and cognitive behaviours, and a glucose tolerance test. In addition, the effects of acute lipopolysaccharide (LPS) challenge on these outcomes were studied.

Results:

ST3ko mice demonstrated deficient motor functions in the wire and pole tests as well as increased anxiety-like behaviour in the open field test, which was also found specifically in females in other anxiety-related tests. Male ST3ko mice had increased locomotion. Moreover, ST3ko mice showed subtle changes in cognitive and social behaviour. Finally, our data suggest deviant metabolic features and altered responses to systemic inflammation and food pellet displacement test in ST3ko mutants.

Conclusions:

Genetic ST3GAL5 deficiency affects motor, emotional and cognitive behaviour, as well as metabolic regulation and neuroinflammation suggesting validity of this mouse model in mimicking clinical aspects ST3GAL5 dysfunction.