title: Deficits in LTP induction by 5-HT2A receptor antagonist in a mouse model for fragile X syndrome.
abstract: Fragile X syndrome is a common inherited form of mental retardation caused by the lack of fragile X mental retardation protein (FMRP) because of Fmr1 gene silencing. Serotonin (5-HT) is significantly increased in the null mutants of Drosophila Fmr1, and elevated 5-HT brain levels result in cognitive and behavioral deficits in human patients. The serotonin type 2A receptor (5-HT2AR) is highly expressed in the cerebral cortex; it acts on pyramidal cells and GABAergic interneurons to modulate cortical functions. 5-HT2AR and FMRP both regulate synaptic plasticity. Therefore, the lack of FMRP may affect serotoninergic activity. In this study, we determined the involvement of FMRP in the 5-HT modulation of synaptic potentiation with the use of primary cortical neuron culture and brain slice recording. Pharmacological inhibition of 5-HT2AR by R-96544 or ketanserin facilitated long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of WT mice. The prefrontal LTP induction was dependent on the activation of NMDARs and elevation of postsynaptic Ca(2+) concentrations. By contrast, inhibition of 5-HT2AR could not restore the induction of LTP in the ACC of Fmr1 knock-out mice. Furthermore, 5-HT2AR inhibition induced AMPA receptor GluR1 subtype surface insertion in the cultured ACC neurons of Fmr1 WT mice, however, GluR1 surface insertion by inhibition of 5-HT2AR was impaired in the neurons of Fmr1KO mice. These findings suggested that FMRP was involved in serotonin receptor signaling and contributed in GluR1 surface expression induced by 5-HT2AR inactivation.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhao-hui
authors.initials: ZH
authors.lastname: Xu
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Lan
authors.initials: L
authors.lastname: Ma
authors.forename: Shui-bing
authors.initials: SB
authors.lastname: Liu
authors.forename: Guang-sheng
authors.initials: GS
authors.lastname: Chen
authors.forename: Yu-mei
authors.initials: YM
authors.lastname: Wu
authors.forename: Xiao-qiang
authors.initials: XQ
authors.lastname: Li
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Ming-gao
authors.initials: MG
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006179:Gyrus Cinguli / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007650:Ketanserin / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D011759:Pyrrolidines / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D007650:Ketanserin; D011759:Pyrrolidines; D044402:Receptor, Serotonin, 5-HT2A; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D058830:Serotonin 5-HT2 Receptor Antagonists; C476157:(2R,4R)-4-hydroxy-2-(2-(2-(2-(3-methoxy)phenyl)ethyl)phenoxy)ethyl-1-methylpyrrolidine hydrochloride; C497684:Fmr1 protein, mouse