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 knock-out (KO) mice lacking FMRP to test the hypothesis that eCB function is altered in FXS. Whole-cell evoked IPSCs (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-dependent inhibitory short-term depression (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 wild-type (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 KO slices 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.
Zhang
Longhua
L
Department of Physiology, Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Alger
Bradley E
BE
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology / Q000502:physiology*; D063388:Endocannabinoids; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000096:biosynthesis / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50
12032354
Neuron. 2005 Aug 4;47(3):339-52
16055059
Nat Neurosci. 2002 Aug;5(8):723-4
12080342
J Neurosci. 2009 Mar 18;29(11):3497-507
19295155
Neuron. 2007 Dec 20;56(6):955-62
18093519
Neuron. 2005 Jan 20;45(2):257-68
15664177
J Med Genet. 1998 Jul;35(7):579-89
9678703
J Neurosci. 2005 Aug 31;25(35):8048-55
16135762
Trends Neurosci. 2004 Jul;27(7):370-7
15219735
J Neurophysiol. 1998 Aug;80(2):989-93
9705485
Science. 2000 May 19;288(5469):1254-7
10818003
J Neurophysiol. 2006 Jan;95(1):67-75
16207781
Hum Mol Genet. 2000 Apr 12;9(6):901-8
10767313
Neuron. 2001 Aug 16;31(3):453-62
11516401
Annu Rev Neurosci. 2002;25:315-38
12052912
J Neurosci. 1999 Jun 1;19(11):4544-58
10341254
Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7168-71
8102206
Nat Rev Neurosci. 2003 Nov;4(11):873-84
14595399
Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20564-9
18077376
Seizure. 2001 Jan;10(1):60-3
11181100
J Physiol. 1998 Oct 1;512 ( Pt 1):61-73
9729617
Cell. 2001 Nov 16;107(4):477-87
11719188
Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8142-7
18523004
J Neurosci. 1997 Mar 1;17(5):1539-47
9030614
Am J Med Genet. 1999 Apr 2;83(4):248-52
10208156
Neuron. 2003 May 8;38(3):461-72
12741992
J Neurosci. 2006 Jul 5;26(27):7147-50
16822970
Neuron. 2001 Aug 16;31(3):463-75
11516402
Neuron. 2006 Aug 17;51(4):441-54
16908410
J Neurosci. 2001 Dec 15;21(24):RC188
11734603
Prog Neurobiol. 2002 Nov;68(4):247-86
12498988