Marilyn Santacruz

Background: Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder that generally affects males more often than females. It is the most common monogenic cause of autism spectrum disorder (ASD) and intellectual disability.¹ FXS is characterized by a disruption in the fragile X messenger ribonucleoprotein 1 (FMR1) gene resulting in the absence of fragile X messenger ribonucleoprotein (FMRP), an RNA-binding protein expressed in most tissues.^2,3 It has been observed that the cyclic adenosine monophosphate (cAMP)-phosphodiesterase pathway is dysregulated in FXS mouse models, and inhibition of phosphodiesterase 2A and 4D (PDE2A and PDE4D, respectively) improves behavioral and synaptic deficits.^2-5 These findings suggest a new therapeutic target for treatment of FXS.

Objective: In this narrative review, we explored the dysregulation of cAMP and phosphodiesterases in FXS and their potential use as therapeutic targets.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2021 using the following keywords: “fragile X syndrome”, “autism spectrum disorder”, “dysregulation”, and “mechanisms”

Results: A study indicated that FMRP negatively regulates the translation and transport of the PDE2A mRNA at the synapse.² An Epac-S^H150 fluorescent biosensor and ratiometric fluorescence imaging were used to monitor changes in cAMP levels in single neurons of the CA1 area of the hippocampus in both FMR1 knockout (KO) and wildtype (WT) mouse brain slices. The cAMP levels observed in FMR1 KO mice were lower than those observed in WT mice,³ which suggests that lack of FMRP increases PDE2A activity in hippocampal neurons. Consistent with this idea, inhibition of PDE2A rescued communicative deficits in the FMR1 KO mice.³ Another study examined behavior in FMR1 KO mice after inhibition of PDE4D which revealed decreased hyperarousal, improved social interaction, as well as improved nesting and marble burying, which are natural behaviors for WT mice.⁴ Furthermore, dendritic spine morphometry revealed an increase in mature spines and a 10% reduction in spine length for layer 3 pyramidal cells in the KO mice. Of significance, the behavioral changes persisted after washout of the drug.⁴ A phase 2 clinical study observed that inhibition of PDE4D in patients with FXS improves daily functioning including language and communication.⁵ There was also observed improvements in recognition, memory, and alertness.⁵ These studies assume that inhibition of PDEs increases the levels of cAMP in the brain.

Conclusion: The absence of FMRP expression in the brain leads to an increase in the translation of phosphodiesterases, such as PDE2A and PDE4D. An increase in PDE activity promotes degradation of the second messenger, cAMP which is involved in important processes such as synaptogenesis and synaptic plasticity. These processes are critical for learning and memory, as well as cognition, all of which are deficient in FXS.

References:

1. Protic DD, Aishworiya R, Salcedo-Arellano MJ, et al. Fragile X syndrome: From molecular aspect to clinical treatment. International Journal of Molecular Sciences. 2022;23(4):1935. doi:10.3390/ijms23041935
2. Maurin T, Lebrigand K, Castagnola S, et al. Hits-clip in various brain areas reveals new targets and new modalities of RNA binding by fragile X mental retardation protein. Nucleic Acids Research. 2018;46(12):6344-6355. doi:10.1093/nar/gky267
3. Maurin T, Melancia F, Jarjat M, et al. Involvement of phosphodiesterase 2A activity in the pathophysiology of fragile X syndrome. Cerebral Cortex. 2018;29(8):3241-3252. doi:10.1093/cercor/bhy192
4. Gurney ME, Cogram P, Deacon RM, Rex C, Tranfaglia M. Multiple behavior phenotypes of the fragile-X syndrome mouse model respond to chronic inhibition of phosphodiesterase-4d (PDE4D). Scientific Reports. 2017;7(1). doi:10.1038/s41598-017-15028-x
5. Berry-Kravis EM, Harnett MD, Reines SA, et al. Inhibition of phosphodiesterase-4d in adults with fragile X syndrome: A randomized, placebo-controlled, phase 2 clinical trial. Nature Medicine. 2021;27(5):862-870. doi:10.1038/s41591-021-01321-w