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Behav Brain Res. 2015 Sep 15;291:164-71. doi: 10.1016/j.bbr.2015.05.003. Epub 2015 May 12.

Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome.

Author information

1
Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 2D54, Bethesda, MD 20892, USA.
2
Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 2D54, Bethesda, MD 20892, USA. Electronic address: beebe@mail.nih.gov.

Abstract

Silencing the gene FMR1 in fragile X syndrome (FXS) with consequent loss of its protein product, FMRP, results in intellectual disability, hyperactivity, anxiety, seizure disorders, and autism-like behavior. In a mouse model (Fmr1 knockout (KO)) of FXS, a deficit in performance on the passive avoidance test of learning and memory is a robust phenotype. We report that drugs acting on the endocannabinoid (eCB) system can improve performance on this test. We present three lines of evidence: (1) Propofol (reported to inhibit fatty acid amide hydrolase (FAAH) activity) administered 30 min after training on the passive avoidance test improved performance in Fmr1 KO mice but had no effect on wild type (WT). FAAH catalyzes the metabolism of the eCB, anandamide, so its inhibition should result in increased anandamide levels. (2) The effect of propofol was blocked by prior administration of the cannabinoid receptor 1 antagonist AM-251. (3) Treatment with the FAAH inhibitor, URB-597, administered 30 min after training on the passive avoidance test also improved performance in Fmr1 KO mice but had no effect on WT. Our results indicate that the eCB system is involved in FXS and suggest that the eCB system is a promising target for treatment of FXS.

KEYWORDS:

FAAH; Fmr1 KO mice; Fragile X syndrome; Memory; Passive avoidance; Propofol

PMID:
25979787
PMCID:
PMC5003021
DOI:
10.1016/j.bbr.2015.05.003
[Indexed for MEDLINE]
Free PMC Article

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