Enhanced endocannabinoid signaling elevates neuronal excitability in Fragile X syndrome

 “Fragile X syndrome (FXS) results from deficiency of fragile X mental retardation protein (FMRP). FXS is the most common heritable form of mental retardation, and is associated with the occurrence of seizures. Factors responsible for initiating FXS-related hyperexcitability are poorly understood. Many protein-synthesis dependent functions of group I metabotropic glutamate receptors (Gp1 mGluRs) are exaggerated in FXS. Gp1 mGluR activation can mobilize endocannabinoids (eCBs) in the hippocampus and thereby increase excitability, but whether FMRP affects eCBs is unknown. We studied Fmr1 knockout (KO) mice lacking FMRP to test the hypothesis that eCB function is altered in FXS. Whole-cell, evoked inhibitory postsynaptic currents (eIPSCs), and field potentials were recorded in the CA1 region of acute hippocampal slices. Three eCB-mediated responses were examined: depolarization-induced suppression of inhibition (DSI), mGluR-initiated eCB short-term depression of eIPSCs (eCB-iSTD), and eCB-dependent inhibitory long-term depression (eCB-iLTD). Low concentrations of a Gp1 mGluR agonist produced larger eCB-mediated responses in Fmr1 KO mice than in WT mice, without affecting DSI. Western blots revealed that levels of mGluR1, mGluR5, or cannabinoid receptor (CB1R), were unchanged in Fmr1 KO animals, suggesting that the coupling between mGluR activation and eCB mobilization was enhanced by FMRP deletion. The increased susceptibility of Fmr1 KOslices to eCB-iLTD was physiologically relevant, since long-term potentiation of epsp-spike (E-S) coupling induced by the mGluR agonist was markedly larger in Fmr1 KO mice than in WT animals. Alterations in eCB signaling could contribute to the cognitive dysfunction associated with FXS…

The endocannabinoid system could represent another target for intervention in the treatment of FXS.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906112/