Haploinsufficiency of the Attention-Deficit/Hyperactivity Disorder Risk Gene St3gal3 in Mice Causes Alterations in Cognition and Expression of Genes Involved in Myelination and Sialylation

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.

Epigenetics and ADHD: Reflections on Current Knowledge, Research Priorities and Translational Potential

“…In humans, mutations in ST3GAL3 have been linked to a range of phenotypes relevant to ADHD (e.g. developmental delays, cognitive and motor impairments [ 67 , 68 ]), and inactivation of this gene in animals results in marked cognitive deficits, reduced motor coordination and hyperactivity [ 69 , 70 ], effects that seem to be largely mediated by disrupted brain myelination, a known neural correlate of ADHD [ 71 ].…”

Epigenetics applied to child and adolescent mental health: Progress, challenges and opportunities

“…Top DNAm sites at birth implicate, among others, genes involved in neural functions (e.g., myelination, neurotransmitter release). The most notable example is ST3GAL3: common variation in this gene has also been identified as a top GWAS hit for ADHD (Demontis et al, 2019;Klein et al, 2019), rare mutations of ST3GAL3 associate with cognitive and motor developmental delays (Khamirani et al, 2021), and ST3GAL3 knockout in mice results in profound cognitive deficits and hyperactivity due to myelination disruption (Rivero et al, 2021). Similar epigenetic timing effects (i.e.,…”

“…Top DNAm sites at birth implicate, among others, genes involved in neural functions (e.g., myelination, neurotransmitter release). The most notable example is ST3GAL3: common variation in this gene has also been identified as a top GWAS hit for ADHD (Demontis et al, 2019;Klein et al, 2019), rare mutations of ST3GAL3 associate with cognitive and motor developmental delays (Khamirani et al, 2021), and ST3GAL3 knockout in mice results in profound cognitive deficits and hyperactivity due to myelination disruption (Rivero et al, 2021). Similar epigenetic timing effects (i.e., where prospective associations at birth show overall a stronger signal in EWAS results than cross-sectional associations in childhood) have also been observed for other neurodevelopmental phenotypes (e.g., social communication deficits (Rijlaarsdam et al, 2021)), but not for broader child mental (e.g., general psychopathology (Rijlaarsdam et al, 2022), sleep problems (Sammallahti et al, 2022)) or physical (e.g., BMI; Vehmeijer et al, 2020) health outcomes, despite studies using largely overlapping data, which points to a degree of phenotypic specificity.…”

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

“…Recently, some of the pathological features were also observed in St3gal3 +/− mice. These mice were shown to have lowered MBP protein expression in the PFC, as well as cognitive deficits in male St3gal3 +/− mice, and increased activity and enhanced cognitive control in female St3gal3 +/− mice [ 64 ].…”