Paradoxical effect of baclofen on social behavior in the fragile X syndrome mouse model.

Shimriet Zeidler,Andreea S Pop,Rob Willemsen,Helen De Boer,Ingeborg Nieuwenhuizen-Bakker,Celine E F De Esch,Ronald A M Buijsen,Renate K Hukema,Israa A Jaafar

doi:10.1002/brb3.991

Abstract

IntroductionFragile X syndrome (FXS) is a common monogenetic cause of intellectual disability, autism spectrum features, and a broad range of other psychiatric and medical problems. FXS is caused by the lack of the fragile X mental retardation protein (FMRP), a translational regulator of specific mRNAs at the postsynaptic compartment. The absence of FMRP leads to aberrant synaptic plasticity, which is believed to be caused by an imbalance in excitatory and inhibitory network functioning of the synapse. Evidence from studies in mice demonstrates that GABA, the major inhibitory neurotransmitter in the brain, and its receptors, is involved in the pathogenesis of FXS. Moreover, several FXS phenotypes, including social behavior deficits, could be corrected in Fmr1 KO mice after acute treatment with GABAB agonists.MethodsAs FXS would probably require a lifelong treatment, we investigated the effect of chronic treatment with the GABAB agonist baclofen on social behavior in Fmr1 KO mice on two behavioral paradigms for social behavior: the automated tube test and the three‐chamber sociability test.ResultsUnexpectedly, chronic baclofen treatment resulted in worsening of the FXS phenotypes in these behavior tests. Strikingly, baclofen treatment also affected wild‐type animals in both behavioral tests, inducing a phenotype similar to that of untreated Fmr1 KO mice.ConclusionAltogether, the disappointing results of recent clinical trials with the R‐baclofen enantiomer arbaclofen and our current results indicate that baclofen should be reconsidered and further evaluated before its application in targeted treatment for FXS.

Highlights

Fragile X syndrome (FXS) is a common monogenetic cause of intellectual disability, autism spectrum features, and a broad range of other psychiatric and medical problems
The assumed involvement of GABAB in social behavior and the fact that chronic treatment might be necessary in the case of FXS prompted us to evaluate chronic baclofen treatment in two social behavioral paradigms: the automated tube test and the three-chamber sociability test
Fragile X syndrome is often characterized by social behavior deficits and autism spectrum features that can significantly impair the patient’s social and adaptive abilities

Summary

| INTRODUCTION

Fragile X syndrome (FXS) is a major X-linked cause of intellectual disability (ID) and autism spectrum disorders (ASD). As many FXS patients manifest social behavior deficits, sleeping disorders, anxiety, and seizures, involvement of the brain’s major inhibitory γ-aminobutyric acid (GABA) pathway has been proposed (D’Hulst & Kooy, 2007). Both the ionotropic GABAA and the metabotropic GABAB receptors have been implicated in FXS and ASD. The assumed involvement of GABAB in social behavior and the fact that chronic treatment might be necessary in the case of FXS prompted us to evaluate chronic baclofen treatment in two social behavioral paradigms: the automated tube test and the three-chamber sociability test Both tests show a paradoxical effect of chronic baclofen treatment on social behavior in Fmr KO mice, worsening their phenotype.

| MATERIALS AND METHODS

Findings

| DISCUSSION