Male-specific cAMP signaling in the hippocampus controls spatial memory deficits in a mouse model of autism and intellectual disability
| Autor: | M. Chiara Manzini, Adam W. Oaks, Pablo Muñoz-Llancao, Molly K. Wilkinson, Heather L. Pond, Adele Mossa, Marta Zamarbide |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Hippocampus Biology CREB Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Intellectual Disability Intellectual disability medicine Cyclic AMP Animals Cyclic adenosine monophosphate Autistic Disorder Biological Psychiatry Spatial Memory Mice Knockout Sex Characteristics Phosphodiesterase medicine.disease Mice Inbred C57BL Repressor Proteins Disease Models Animal 030104 developmental biology chemistry Autism spectrum disorder biology.protein Autism Female Neuroscience 030217 neurology & neurosurgery Intracellular Signal Transduction |
| Zdroj: | Biol Psychiatry |
| Popis: | Background The prevalence of neurodevelopmental disorders is biased toward male individuals, with male-to-female ratios of 2:1 in intellectual disability and 4:1 in autism spectrum disorder. 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 protein 1A (CC2D1A), which is mutated in intellectual disability and autism spectrum disorder, we identified biochemical and behavioral differences between male and female mice, and explored whether CC2D1A controls male-specific intracellular signaling. Methods CC2D1A is known to regulate phosphodiesterase 4D (PDE4D), which regulates cyclic adenosine monophosphate (cAMP) signaling. We tested for activation of PDE4D and downstream signaling molecules in the hippocampus of Cc2d1a-deficient mice. We then performed behavioral studies in female mice to analyze learning and memory, and then targeted PDE4D activation with a PDE4D inhibitor to define how changes in cAMP levels affect behavior in male and female mice. Results We found that in Cc2d1a-deficient male mice PDE4D is hyperactive, leading to a reduction in cAMP response element binding protein signaling, but this molecular deficit is not present in female mice. Cc2d1a-deficient male mice show a deficit in spatial memory, which is not present in Cc2d1a-deficient female mice. Restoring PDE4D activity using an inhibitor rescues cognitive deficits in male mice but has no effect on female mice. Conclusions Our findings show that CC2D1A regulates cAMP intracellular signaling in a male-specific manner in the hippocampus, leading to male-specific cognitive deficits. We propose that male-specific signaling mechanisms are involved in establishing sex bias in neurodevelopmental disorders. |
| Databáze: | OpenAIRE |
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