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

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.

Hyperexcitability and Homeostasis in Fragile X Syndrome

“…Arbaclofen has indeed been shown to normalize protein synthesis rates as well as a variety of physiological and behavioral phenotypes in FMR1 KO mice (Henderson et al, 2012 ; Silverman et al, 2015 ; Sinclair et al, 2017a ). However, clinical trials with arbaclofen have proved unsuccessful (Berry-Kravis et al, 2017 ) and recent animal studies found that chronic baclofen treatment can actually result in exacerbation of FXS phenotypes, potentially due to drug tolerance development (Zeidler et al, 2018 ). Drug tolerance development may also limit the effectiveness of other potential FXS therapies, like mGluR5 inhibitors (Stoppel et al, 2021 ).…”

Role of FMRP in rapid antidepressant effects and synapse regulation

“…Paradoxically, clinical trials suggest that treatment with the GABA B R agonist baclofen improves irritability and social responsiveness in people with FXS and ASD; however, these results are mixed [ 50 – 52 ]. Moreover, baclofen can cause adverse side effects, including hyperactivity and anxiety in FXS patients [ 53 – 55 ]. Our results raise the question of why GABA B R signaling is required for synaptogenesis and antidepressant efficacy in WT mice yet prohibitive in Fmr1 KO mice.…”

Role of FMRP in rapid antidepressant effects and synapse regulation

“…While clinical trials demonstrate that treatment with the GABAB agonist baclofen improves irritability and social responsiveness in people with FXS and ASD, these results are mixed [41][42][43] . Additionally, baclofen can cause adverse side effects, including hyperactivity and anxiety [44][45][46] . These data, in light of our results, raise the question as to why GABABR signaling is required for synaptogenesis and antidepressant efficacy in WT mice, yet prohibitive in Fmr1 KO mice.…”