Carbamazepine Restores Neuronal Signaling, Protein Synthesis, and Cognitive Function in a Mouse Model of Fragile X Syndrome.

Qi Ding,Hongbing Wang,Yue Feng,Fan Zhang

doi:10.3390/ijms21239327

Abstract

Fragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, it is widely accepted that the lack of FMRP causes elevated protein synthesis and deregulation of neuronal signaling. Abnormal enhancement of the ERK½ (extracellular signal-regulated kinase ½) and PI3K-Akt (Phosphoinositide 3 kinase-protein kinase B) signaling pathways has been identified in both FXS patients and FXS mouse models. In this study, we show that carbamazepine, which is an FDA-approved drug and has been mainly used to treat seizure and neuropathic pain, corrects cognitive deficits including passive avoidance and object location memory in FXS mice. Carbamazepine also rescues hyper locomotion and social deficits. At the cellular level, carbamazepine dampens the elevated level of ERK½ and Akt signaling as well as protein synthesis in FXS mouse neurons. Together, these results advocate repurposing carbamazepine for FXS treatment.

Highlights

Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism
With regard to understanding how alteration of fragile X mental retardation protein (FMRP)-regulated translation is linked to elevated ERKERK1⁄2 activity, it is found that FMRP binds Adcy1 mRNA [8,9], and ADCY1 protein level is elevated in Fmr1 knockout (KO) mice [10]
We demonstrated that inhibition of ADCY1 by carbamazepine can correct abnormal ERKERK1⁄2 and Akt signaling, protein synthesis, and the core symptoms of cognitive deficits in a mouse model of FXS

Summary

Introduction

Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Previous studies have found that activity of the ERKERK1⁄2 signaling pathway is abnormally enhanced in FXS mouse model (i.e., Fmr knockout mouse) and human patient samples [5,6,7]. Consistent with the finding that enhancement of ADCY1 expression causes elevated ERKERK1⁄2 activity [11] and a panel of FXS-associated behavior (e.g., hyperlocomotion and social deficits) [12], genetic reduction of Adcy attenuates the elevated ERKERK1⁄2 signaling and the aforementioned behavioral abnormalities in Fmr KO mice [10]. Genetic reduction of Adcy restores Akt signaling [10], the activity of which is elevated in both human patient and FXS mouse samples [7,13,14] These observations suggest that aberrant hyperfunction of ADCY1 in FXS is a potential therapeutic target, through which the pathological overactivation of both ERKERK1⁄2 and Akt signaling pathways can be corrected. The potential therapeutic value in clinical application requires examination with practical pharmacological intervention

Methods

Results

Conclusion