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

Marta Zamarbide, Adele Mossa, Molly K Wilkinson, Heather L Pond, Adam W Oaks, M. Chiara Manzini
2018 bioRxiv   pre-print
The 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
more » ... ored whether CC2D1A controls male-specific intracellular signaling. Methods: CC2D1A 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. Results: We 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. Conclusions: Our 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.
doi:10.1101/249649 fatcat:ute2g3dxozd3dldxuyskievnc4