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

• Published in: PloS one Vol. 7; no. 10; p. e48741
• Main Authors: Xu, Zhao-hui, Yang, Qi, Ma, Lan, Liu, Shui-bing, Chen, Guang-sheng, Wu, Yu-mei, Li, Xiao-qiang, Liu, Gang, Zhao, Ming-gao
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.10.2012; Public Library of Science (PLoS)
• Subjects: Animals; Behavioral plasticity; Biology; Blotting, Western; Brain; Brain slice preparation; Calcium; Cell culture; Cells, Cultured; Cerebral cortex; Cognitive ability; Cortex (cingulate); Deactivation; Disease Models, Animal; Dopamine; Drosophila; FMR1 protein; Fragile X mental retardation protein; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X Mental Retardation Protein - physiology; Fragile X syndrome; Fragile X Syndrome - genetics; Fragile X Syndrome - metabolism; Fragile X Syndrome - physiopathology; Fruit flies; GABA; Gene silencing; Genetic engineering; Glutamic acid receptors (ionotropic); Gyrus Cinguli - cytology; Gyrus Cinguli - metabolism; Gyrus Cinguli - physiology; Human behavior; Humans; Inactivation; Inhibition; Insertion; Intellectual disabilities; Interneurons; Ketanserin; Ketanserin - pharmacology; Kinases; Long-term potentiation; Long-Term Potentiation - drug effects; Long-Term Potentiation - genetics; Long-Term Potentiation - physiology; Male; Medicine; Mental disorders; Mice; Mice, 129 Strain; Mice, Knockout; Mutants; N-Methyl-D-aspartic acid receptors; Neural plasticity; Neurons; Patch-Clamp Techniques; Pharmacology; Pharmacy; Potentiation; Prefrontal cortex; Proteins; Pyramidal cells; 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; Rodents; Serotonin; Serotonin 5-HT2 Receptor Antagonists - pharmacology; Serotonin S2 receptors; Signaling; Studies; Synaptic plasticity; Synaptic Potentials - drug effects; Synaptic Potentials - physiology; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; γ-Aminobutyric acid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0048741

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.