Abstract
Genome wide association meta-analysis identified ST3GAL3, a gene encoding the beta-galactosidase-alpha-2,3-sialyltransferase-III, as a risk gene for attention-deficit/hyperactivity disorder (ADHD). Although loss-of-function mutations in ST3GAL3 are implicated in non-syndromic autosomal recessive intellectual disability (NSARID) and West syndrome, the impact of ST3GAL3 haploinsufficiency on brain function and the pathophysiology of neurodevelopmental disorders (NDDs), such as ADHD, is unknown. Since St3gal3 null mutant mice display severe developmental delay and neurological deficits, we investigated the effects of partial inactivation of St3gal3 in heterozygous (HET) knockout (St3gal3±) mice on behavior as well as expression of markers linked to myelination processes and sialylation pathways. Our results reveal that male St3gal3 HET mice display cognitive deficits, while female HET animals show increased activity, as well as increased cognitive control, compared to their wildtype littermates. In addition, we observed subtle alterations in the expression of several markers implicated in oligodendrogenesis, myelin formation, and protein sialylation as well as cell adhesion/synaptic target glycoproteins of ST3GAL3 in a brain region- and/or sex-specific manner. Taken together, our findings indicate that haploinsufficiency of ST3GAL3 results in a sex-dependent alteration of cognition, behavior and markers of brain plasticity.
Highlights
Neurodevelopmental disorders (NDDs) constitute frequent causes of disability among children and adolescents world-wide
By using polymerase chain reaction (PCR) primers located in exons 2 and 3 targeting the St3gal3 WT allele, we observed a gene dose dependent reduction of ∼50% in St3gal3 levels in HET mice when compared to WT littermates, in all analyzed brain regions (p < 0.0001) (Figure 2)
We evaluated the effects of St3gal3 haploinsufficiency using the Intellicage System, which allows the assessment of different behavioral domains that are related to attentiondeficit/hyperactivity disorder (ADHD) pathophysiology
Summary
Neurodevelopmental disorders (NDDs) constitute frequent causes of disability among children and adolescents world-wide. ST3GAL3 was implicated in general cognitive function in a GWAS meta-analysis (Davies et al, 2018) Together, these findings identify ST3GAL3 as a putative risk gene for ADHD, for associated impairment of cognitive performance. The authors reported alterations in different markers linked to oligodendrogenesis and the process of myelination (MBP, Olig, and MAG) They reported reduced motor coordination, marked cognitive deficits and hyperactive behavior in St3gal single-null mice. With the guidelines for animal care and use provided by the European Parliament and Council Directive (2010/63/EU)
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