Mice which mimic the genetic alteration in Fragile X syndrome (FXS), such as the Fmr1 knockout (Fmr1-KO) mouse, allow scientists to study the alterations derived from the mutation and assess novel potential therapeutic strategies. Our team first identified the cannabinoid type-1 receptor (CB1R) as a potential treatment target for FXS. Inhibiting this receptor improved learning as well as neurological features in Fmr1-KO mice. 

Recently our team identified molecular features (transcriptional profile) that constitute a Fragile X molecular signature (FX-MS) for Fmr1-KO mice. This FX-MS is significantly modified by a cognition-improving pharmacological treatment which targets CB1R. This in turn allowed us to identify a treatment-dependent molecular signature (T-MS).

In this project, we plan to extend our unbiased molecular analysis to test three potential FXS treatments (BPN14770, CTEP, and cannabidiol), all of which improve memory performance in Fragile X knockout mice. Additionally, we will further assess the molecular signature in neuron-derived extracellular vesicles obtained from the same mice exposed to treatment. We will look for signatures of treatment resistance (drug tolerance), since this potential drawback has been described for repeated intervention with CTEP. Importantly, the translational relevance of the FX-MS will be extended with the study of molecular signatures in post-mortem hippocampal tissues from subjects with FXS and matched controls.

Together, our experiments will identify translational molecular signatures for FXS that are sensitive to pharmacological approaches found to resolve cognitive deficits in Fmr1-KO mice. The expected results will enable us to define biomarkers to be used in clinical settings as measures of treatment efficacy and/or resistance.