👤 Kerri M Sparkes

Although increased maternal androgens, such as those in polycystic ovary syndrome (PCOS), are associated with a higher incidence of autism spectrum disorder (ASD) in offspring, a causal link has yet to be established. We assessed whether perinatal hyperandrogenization in a murine model recapitulates core ASD traits and compared this model to the maternal immune activation (MIA) model of ASD. Both models produced ASD-like phenotypes, yet they exhibited distinct behavioral subtypes and neurodevelopmental trajectories. Hyperandrogenized offspring showed greater reductions in social communication (neonatal USVs, d = 0.633-0.773; juvenile USVs, d = 1.103-1.216; social preference, d = 0.715), whereas only MIA offspring showed increased repetitive behaviors (d = 0.599). Ex vivo magnetic resonance imaging revealed volume increases in specific cortical regions in both models, with MIA additionally showing absolute cingulate cortex enlargement, and hyperandrogenized mice displaying focal increases in sexually dimorphic regions, despite a 36% reduction in overall brain volume (FDR 10%). Placentas from both groups showed reduced LIX (CXCL5), but distinct immune shifts also emerged: MIA placentas exhibited elevated IL-4 and IL-1β, whereas hyperandrogenized placentas showed increased TNFα. In neonatal brains, both conditions were associated with reduced IL-2, with MIA additionally decreasing IL-17A and IL-12p70, suggesting suppression of Th1/Th17-type cytokine signaling that normally supports proinflammatory and immune-neural interactions. DRD2 and BDNF protein were upregulated in hyperandrogenized fetal brains but downregulated with MIA. These results suggest that hyperandrogenization and MIA act through distinct mechanisms, producing subtle neurodevelopmental and behavioral differences consistent with human ASD subtypes. Show less

The physical environment modulates the maternal brain and affects maternal-offspring dynamics, with downstream effects on neonatal development. In this study, we examined whether environmental enrichment (EE) influences maternal approach, neonatal ultrasonic vocalizations (USVs), and early neuroendocrine development in mice, focusing on hormonal pathways associated with maternity, stress responsivity, and gonadal hormones. Nulliparous female C57BL/6 mice were housed in EE or standard (ST) conditions prior to mating. EE cages were larger and contained extra bedding and enrichment items. Litters were culled to four pups (2/sex), and maternal approach and pup USVs were recorded on postnatal days (PND) 6 and 8 using a modified three-chamber protocol. EE dams made fewer entries into female interaction zones than ST counterparts. EE also increased USV call numbers and decreased call frequencies among pups. These effects were not sex-dependent, and despite higher emission rates, USV parameters did not correlate with maternal response in the EE group. Gene expression analyses revealed that EE altered stress- and care-related genes in the maternal brain, downregulating Prlr (prolactin receptor) and Nr3c2 (mineralocorticoid receptor) in the cortex and upregulating Prlr while downregulating Nr3c2 and Oxtr (oxytocin receptor) in the diencephalon. Further, EE housing changed neuroendocrine profiles in male pups, but not females, suggesting benefits to neurodevelopment (increased brain-derived neurotrophic factor) and alterations to sexual differentiation (Ar [androgen receptor] and Esr1 [estrogen receptor alpha]) and stress reactivity (Nr3c1 [glucocorticoid receptor] and Nr3c2). These findings highlight how environmental context can shape maternal brain and behaviour and imprint on offspring neuroendocrine development in a sex-dependent manner. Show less

The chromosomal loci for seven epilepsy genes have been identified in chromosomes 1q, 6p, 8q, 16p, 20q, 21q, and 22q. In 1987, the first epilepsy locus was mapped in a common benign idiopathic generalized epilepsy syndrome, juvenile myoclonic epilepsy (JME). Properdin factor or Bf, human leukocyte antigen (HLA), and DNA markers in the HLA-DQ region were genetically linked to JME and the locus, named EJM1, was assigned to the short arm of chromosome 6. Our latest studies, as well as those by Whitehouse et al., show that not all families with JME have their genetic locus in chromosome 6p, and that childhood absence epilepsy does not map to the same EJM1 locus. Recent results, therefore, favor genetic heterogeneity for JME and for the common idiopathic generalized epilepsies. Heterogeneity also exists in benign familial neonatal convulsions, a rare form of idiopathic generalized epilepsy. Two loci are now recognized; one in chromosome 20q (EBN1) and another in chromosome 8q. Heterogeneity also exists for the broad group of debilitating and often fatal progressive myoclonus epilepsies (PME). The gene locus (EPM1) for both the Baltic and Mediterranean types of PME or Unverricht-Lundborg disease is the same and is located in the long arm of chromosome 21. Lafora type of PME does not map to the same EPM1 locus in chromosome 21. PME can be caused by the juvenile type of Gaucher's disease, which maps to chromosome 1q, by the juvenile type of neuronal ceroid lipofuscinoses (CLN3), which maps to chromosome 16p, and by the "cherry-red-spot-myoclonus" syndrome of Guazzi or sialidosis type I, which has been localized to chromosome 10. A point mutation in the mitochondrial tRNA(Lys) coding gene can also cause PME in children and adults (MERFF). Show less