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

Abstract

BackgroundThe prevalence of neurodevelopmental disorders is biased towards males with male: female ratios of 2:1 in intellectual disability (ID) and 4:1 in autism spectrum disorder (ASD). However, the molecular mechanisms of such bias remain unknown. While characterizing a mouse model for loss of the signaling scaffold coiled-coil and C2 domain containing 1A (CC2D1A), which is mutated in ID and ASD, we identified biochemical and behavioral differences between males and females, and explored whether CC2D1A controls male-specific intracellular signaling.MethodsCC2D1A is known to regulate phosphodiesterase 4D (PDE4D). We tested for activation PDE4D and downstream signaling molecules such as CREB in the hippocampus of Cc2d1a-deficient mice. We then performed behavioral studies in females to analyze learning and memory, social interactions, anxiety and hyperactivity. Finally, we targeted PDE4D activation with a PDE4D inhibitor to define how changes in PDE4D and CREB activity affect behavior in males and females.ResultsWe found that in Cc2d1a-deficient males PDE4D is hyperactive leading to a reduction in CREB signaling, but this molecular deficit is not present in females. Cc2d1a-deficient females only show impairment in novel object recognition, and no other cognitive and social deficits that have been found in males. Restoring PDE4D activity using an inhibitor rescues male-specific cognitive deficits, but has no effect on females.ConclusionsOur findings show that CC2D1A regulates intracellular signaling in a male-specific manner in the hippocampus leading to male-specific behavioral deficits. We propose that male-specific signaling mechanisms are involved in establishing sex bias in neurodevelopmental disorders.

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.…”