Paradoxical effect of baclofen on social behavior in the fragile X syndrome mouse model
| Autor: | Celine de Esch, Andreea S. Pop, Renate K. Hukema, Israa A. Jaafar, Ronald A.M. Buijsen, Shimriet Zeidler, Helen de Boer, Rob Willemsen, Ingeborg Nieuwenhuizen-Bakker |
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| Přispěvatelé: | Clinical Genetics |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Baclofen congenital hereditary and neonatal diseases and abnormalities Neuropsychological Tests Inhibitory postsynaptic potential Fragile X Mental Retardation Protein Mice 03 medical and health sciences Behavioral Neuroscience chemistry.chemical_compound 0302 clinical medicine Postsynaptic potential medicine Animals RNA Messenger Social Behavior Mice Knockout business.industry medicine.disease FMR1 Mice Inbred C57BL Fragile X syndrome Disease Models Animal 030104 developmental biology nervous system chemistry Fragile X Syndrome GABA-B Receptor Agonists Synapses Synaptic plasticity Excitatory postsynaptic potential Autism business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Brain and Behavior, 8(6):e00991. John Wiley & Sons Inc. |
| ISSN: | 2162-3279 |
| Popis: | textabstractIntroduction: 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. |
| Databáze: | OpenAIRE |
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