Abnormal mGlu 5 receptor/endocannabinoid coupling in mice lacking FMRP and BC1 RNA.
Transcriptional silencing of the gene encoding the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP acts as a translational repressor at central synapses, and molecular and synaptic plasticity studies have shown that the absence of this protein alters metabotropic glutamate 5 receptors (mGlu5Rs)-mediated signaling. In the striatum of mice lacking FMRP, we found enhanced activity of diacylglycerol lipase (DAGL), the enzyme limiting 2-arachidonoylglicerol (2-AG) synthesis, associated with altered sensitivity of GABA synapses to the mobilization of this endocannabinoid by mGlu5R stimulation with DHPG. Mice lacking another repressor of synaptic protein synthesis, BC1 RNA, also showed potentiated mGlu5R-driven 2-AG responses, indicating that both FMRP and BC1 RNA act as physiological constraints of mGlu5R/endocannabinoid coupling at central synapses. The effects of FMRP ablation on DAGL activity and on DHPG-mediated inhibition of GABA synapses were enhanced by simultaneous genetic inactivation of FMRP and BC1 RNA. In double FMRP and BC1 RNA lacking mice, striatal levels of 2-AG were also enhanced compared with control animals and to single mutants. Our data indicate for the first time that mGlu5R-driven endocannabinoid signaling in the striatum is under the control of both FMRP and BC1 RNA. The abnormal mGlu5R/2-AG coupling found in FMRP-KO mice emphasizes the involvement of mGlu5Rs in the synaptic defects of FXS, and identifies the modulation of the endocannabinoid system as a novel target for the treatment of this severe neuropsychiatric disorder.
Maccarrone
Mauro
M
Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, Teramo, Italy. mmaccarrone@unite.it
Rossi
Silvia
S
Bari
Monica
M
De Chiara
Valentina
V
Rapino
Cinzia
C
Musella
Alessandra
A
Bernardi
Giorgio
G
Bagni
Claudia
C
Centonze
Diego
D
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D063388:Endocannabinoids; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D005989:Glycerides / Q000378:metabolism; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008071:Lipoprotein Lipase / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D020733:RNA, Small Cytoplasmic / Q000235:genetics*; D018092:Kainic Acid Receptors / Q000378:metabolism*; D018709:Statistics, Nonparametric
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D013759:Dronabinol; D063388:Endocannabinoids; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D005989:Glycerides; D008071:Lipoprotein Lipase; D008734:Methoxyhydroxyphenylglycol; D010880:Piperidines; D011720:Pyrazoles; D020733:RNA, Small Cytoplasmic; D018092:Kainic Acid Receptors; C117734:BC1 RNA; C497684:Fmr1 protein, mouse; C103505:AM 251; C094503:glyceryl 2-arachidonate; C062018:HU 211; C010117:3,4-dihydroxyphenylglycol
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