Reduced synaptic function of Kainate receptors in the insular cortex of Fmr1 Knock-out mice

Shuang Qiu,Kohei Koga,Xia Li,Yu Wu,Min Zhuo,Xinyou Lv

doi:10.1186/s13041-018-0396-1

Abstract

Fragile X syndrome is caused by the loss of fragile X mental retardation protein (FMRP). Kainate receptor (KAR) is a subfamily of ionotropic glutamate receptors (iGluR) that acts mainly as a neuromodulator of synaptic transmission and neuronal excitability. However, little is known about the changes of synaptic KAR in the cortical area of Fmr1 KO mice. In this study, we performed whole-cell patch-clamp recordings from layer II/III pyramidal neurons in the insular cortex of Fmr1 KO mice. We found that KARs mediated currents were reduced in Fmr1 KO mice. KARs were mainly located in the synaptosomal fraction of the insular cortex. The abundance of KAR subunit GluK1 and GluK2/3 in the synaptosome was reduced in Fmr1 KO mice, whereas the total expressions of these KARs subunits were not changed. Finally, lack of FMRP impairs subsequent internalization of surface GluK2 after KAR activation, while having no effect on the surface GluK2 expression. Our studies provide evidence indicating that loss of FMRP leads to the abnormal function and localization of KARs. This finding implies a new molecular mechanism for Fragile X syndrome.

Highlights

Fragile X syndrome (FXS) is the most common monogenic cause of autism and inherited mental impairment [1, 2]
Subcellular distribution of Kainate receptor (KAR) in the insular cortex We examined the subcellular distribution of KARs in the insular cortex of fragile X mental retardation 1 (Fmr1) WT mice by synaptosome fractionation
In addition to metabotropic glutamate receptors (mGluR), ionotropic glutamate receptors (iGluRs) are regulated by fragile X mental retardation protein (FMRP)

Summary

Introduction

Fragile X syndrome (FXS) is the most common monogenic cause of autism and inherited mental impairment [1, 2]. The FXS is almost exclusively caused by an expansion of a trinucleotide repeat (CGG) repeat in the 5′ untranslated region of the X-linked fragile X mental retardation 1 (Fmr1) gene. Mutation in the Fmr gene leads to a failure to express the fragile X mental retardation protein (FMRP), which functions in repressing local translation at the synapse and regulating mRNA trafficking and stability [3–7]. Fmr knockout (KO) mice are sufficient to generate a mouse model for FXS and exhibit cognitive deficits and abnormal plasticity in the cortex or hippocampus. Local protein synthesis is required for long-term synaptic plasticity that stores memories and is orchestrated by the action of glutamate receptors. Activation of metabotropic glutamate receptors (mGluR) produces long-term

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Conclusion