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

2018; Wiley; Volume: 8; Issue: 6 Linguagem: Inglês

10.1002/brb3.991

2162-3279

Shimriet Zeidler, Andreea Pop, Israa A. Jaafar, Helen de Boer, Ronald A.M. Buijsen, Celine de Esch, Ingeborg Nieuwenhuizen‐Bakker, Renate K. Hukema, Rob Willemsen,

Epigenetics and DNA Methylation

Abstract 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 mRNA s 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 GABA B agonists. Methods As FXS would probably require a lifelong treatment, we investigated the effect of chronic treatment with the GABA B 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 .