Genome wide association meta-analysis identified ST3GAL3, a gene encoding
the beta-galactosidase-alpha-2,3-sialyltransferase-III, as a risk gene for attentiondeficit/
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.