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

Introduction 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. 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. Methods As 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. Results Unexpectedly, 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. Conclusion Altogether, 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. This paper describes the results of chronic baclofen treatment in FXS mouse model. In contrast to earlier promising reports on acute baclofen treatment, our results show that chronic treatment leads to an adverse effect on social behavior. This might explain the recent failure of clinical trials with patients with FXS using arbaclofen.