Deficits in LTP induction by 5-HT2A receptor antagonist in a mouse model for fragile X syndrome

PLoS One. 2012;7(10):e48741. doi: 10.1371/journal.pone.0048741. Epub 2012 Oct 31.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Mental Retardation Protein / physiology*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism
  • Fragile X Syndrome / physiopathology*
  • Gyrus Cinguli / cytology
  • Gyrus Cinguli / metabolism
  • Gyrus Cinguli / physiology
  • Humans
  • Ketanserin / pharmacology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / genetics
  • Long-Term Potentiation / physiology*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • Patch-Clamp Techniques
  • Pyrrolidines / pharmacology
  • Receptor, Serotonin, 5-HT2A / genetics
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Receptor, Serotonin, 5-HT2A / physiology*
  • Receptors, AMPA / metabolism
  • Receptors, AMPA / physiology
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology
  • Synaptic Potentials / drug effects
  • Synaptic Potentials / physiology

Substances

  • (2R,4R)-4-hydroxy-2-(2-(2-(2-(3-methoxy)phenyl)ethyl)phenoxy)ethyl-1-methylpyrrolidine hydrochloride
  • Fmr1 protein, mouse
  • Pyrrolidines
  • Receptor, Serotonin, 5-HT2A
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Serotonin 5-HT2 Receptor Antagonists
  • Fragile X Mental Retardation Protein
  • Ketanserin
  • glutamate receptor ionotropic, AMPA 1

Grants and funding

This project was supported by National Natural Science Foundation of China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.