Sex-Specific ADHD-like Behaviour, Altered Metabolic Functions, and Altered EEG Activity in Sialyltransferase ST3GAL5-Deficient Mice

Abstract

A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5−/−) mice lack a-, b-, and c-series gangliosides, but exhibit no overt neuropathology, possibly owing to the production of compensatory 0-series glycosphingolipids. Here, we sought to investigate the possibility that St3gal5−/− mice might exhibit attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In addition, we evaluated potential metabolic and electroencephalogram (EEG) abnormalities. St3gal5−/− mice were subjected to behavioural testing, glucose tolerance tests, and the levels of expression of brain and peripheral A and B isoforms of the insulin receptor (IR) were measured. We found that St3gal5−/− mice exhibit locomotor hyperactivity, impulsivity, neophobia, and anxiety-like behavior. The genotype also altered blood glucose levels and glucose tolerance. A sex bias was consistently found in relation to body mass and peripheral IR expression. Analysis of the EEG revealed an increase in amplitude in St3gal5−/− mice. Together, St3gal5−/− mice exhibit ADHD-like behaviours, altered metabolic and EEG measures providing a useful platform for better understanding of the contribution of brain gangliosides to ADHD and associated comorbidities.

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

“…Naïve St3gal5 −/− male mice exhibited a substantial increase in dominant behaviour, and a similar trend was also found in St3gal5 −/− female mice. Behavioural alterations were accompanied by increased mRNA expression of pro-inflammatory cytokine interleukin-1β (Il-1β) and tumour necrosis factor (Tnf), both in the prefrontal cortex (PFC) and the spleen of St3gal5 −/− animals ( Figure 1 , for methods see [ 57 ]).…”

“…In another study we found increased locomotor activity in mutants of both sexes, as well as elevated anxiety-like behaviour and decreased exploratory behaviour [ 57 ]. These changes were accompanied by alterations in the expression of insulin receptor (IR) isoforms in the spleen and liver; in male mice, mRNA expression of both the A and B isoforms of IR was increased in wild type animals compared to mutants in both the liver and spleen, while in females, IR-B expression was increased in the livers of mutants.…”

“…The body weight of male mutants was significantly increased compared to male control mice. Additionally, we found an increased number of high-amplitude EEG spikes [ 57 ], which we speculated to be representative of seizures observed in some of the patients with ganglioside metabolism disorders.…”

“…In our recent study, we found decreased expression of IRs in the spleen and the liver of St3gal5 −/− male mice accompanied by an increase in body weight, suggesting metabolic changes [ 57 ]. Previously, changes in IR signalling in adipose tissue and skeletal muscle were also found in these mice [ 51 ].…”

“…Mice were euthanized, perfused with saline, and their brains and spleens were dissected and frozen at −70 °C for qPCR assay. Full description of the study can be found in [ 57 ]; for primer sequences, see [ 56 ]. WT—wild-type mice.…”