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

Tatyana Strekalova,Sharafuddin Khairuddin,Ekaterina Veniaminova,Evgeniy Svirin,Eugene D Ponomarev,Andrey Proshin,Klaus-Peter Lesch,Amanda W Y Yung,Daniel C Anthony,Lee Wei Lim,Susanne Walitza,Ekaterina Kopeikina,Shawn Zheng Kai Tan,Tatyana Veremeyko

doi:10.3390/biom11121759

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.

Highlights

Gangliosides are critically involved in protein organization [1,2], signaling, adhesion, and brain development by regulating myelination, insulin receptor function, immunity, and other processes [3,4,5]
Independent cohorts were examined for the open field, elevated plus maze, dark/light box, novel object exploration, three-chamber social exploration and tail suspension behaviours, body weight, mRNA levels of IRA and IRB isoforms in the brain cortex and spleen, and brain cortex EEG-parameters
A two-way ANOVA revealed that total distance traveled and the speed in the central zone of the open field (p < 0.05, Figure 1A,B) was increased in the St3gal5−/− mice compared with wild-type mice

Summary

Introduction

Gangliosides are critically involved in protein organization [1,2], signaling, adhesion, and brain development by regulating myelination, insulin receptor function, immunity, and other processes [3,4,5]. Alpha-2,3-sialyltransferase 5 (ST3GAL5) is responsible for the production of GM3, which represents the root structure for 90% of the gangliosides (i.e., GM1, GD1a, GD1b, and GT1b) in the human brain. Biallelic transmission of rare variants of encoding the ST3GAL5 gene leads to an absence of GM3 synthesis and serious neuropathology [6]. GWAS have reported associations between SNPs encoding ST3GAL3 and the incidence of schizophrenia, attention-deficit/hyperactivity disorder (ADHD) and autistic spectrum disorders (ASD) [7,8]. The ganglioside expression pattern has been proposed as a biomarker of schizophrenia [1,5]

Methods

Results

Conclusion