Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders

Abstract

Neurodevelopmental disorders, including autism spectrum disorders, are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders. Here we report male-specific deficits in striatal function important to reward learning in a mouse model of 16p11.2 hemideletion, a genetic mutation that is strongly associated with the risk of neurodevelopmental disorders, particularly autism and attention-deficit hyperactivity disorder. We find that male, but not female, 16p11.2 deletion animals show impairments in reward-directed learning and maintaining motivation to work for rewards. Male, but not female, deletion animals overexpress mRNA for dopamine receptor 2 and adenosine receptor 2a in the striatum, markers of medium spiny neurons signaling via the indirect pathway, associated with behavioral inhibition. Both sexes show a 50% reduction of mRNA levels of the genes located within the 16p11.2 region in the striatum, including the kinase extracellular-signal related kinase 1 (ERK1). However, hemideletion males show increased activation in the striatum for ERK1, both at baseline and in response to sucrose, a signaling change associated with decreased striatal plasticity. This increase in ERK1 phosphorylation is coupled with a decrease in the abundance of the ERK phosphatase striatum-enriched protein-tyrosine phosphatase in hemideletion males. In contrast, females do not show activation of ERK1 in response to sucrose, but notably hemideletion females show elevated protein levels for ERK1 as well as the related kinase ERK2 over what would be predicted by mRNA levels. These data indicate profound sex differences in the impact of a genetic lesion linked with neurodevelopmental disorders, including mechanisms of male-specific vulnerability and female-specific resilience impacting intracellular signaling in the brain.

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

“…We observed coordinated expression of Prkaca, Grina and Adora1a genes in active D1 MSNs. Their relation to D1 neurons was reported previously [14], along with Grin1, Map2k1/Mapk3 (ERK1) and Map2k5/Mapk7 (ERK5) genes [41], which were also localized in this cluster in our study.…”

Male-specific CREB signaling in the hippocampus controls spatial memory deficits in a mouse model of autism and intellectual disability

“…On the other hand, females require more severe rare genetic mutations and more familial risk factors than males to become affected (43,44), supporting the hypothesis that females are protected. Our findings in Cc2d1a cKO mice, together with those from Grissom et al in a 16p11.2 hemideletion model (15), reveal that sex-specific disruptions in intracellular signaling may be involved in establishing malespecific behavioral phenotypes. While these findings do not yet define whether males are susceptible or females are protected, they show that in inbred genetic models recapitulating human mutations equally in males and females, males develop sex-specific signaling deficits.…”

“…CREB activity in the hippocampus is critical for memory formation and retrieval (13,14), and studies in primary hippocampal neurons showed that CREB is primarily controlled by estrogen receptor activation in female neurons, and not in males (11). A study in a mouse model of 16p11.2 deletion syndrome found male specific hyperactivity in MAPK3/ERK1 kinase in the striatum correlating with male-specific striatal learning deficits (15), suggesting a possible link between sex-specific signaling and behavior.…”

The autism-associated gene Scn2a plays an essential role in synaptic stability and learning

“…Whether female Scn2a +/- are similarly resistant to spatial learning impairments has not been explored. Nevertheless, these data add to a growing body of literature highlighting sex-based differences in the behavior of neurodevelopmental disorder models (Angelakos et al, 2017; Dhamne et al, 2017; Grissom et al, 2018; Reith et al, 2013; Schmeisser et al, 2012; Zamarbide et al, 2018), paralleling the sex biases observed in ASD and, to a lesser extent, ID (Fischbach and Lord, 2010; Kim et al, 2011). While we provide insight into how cortical physiology is altered by Scn2a loss, future work will be needed to elucidate the cellular and synaptic consequences of Scn2a haploinsufficiency in regions outside of PFC, and whether region-specific impairments underlie behavioral deficits in a sex-specific manner.…”