Synaptic ionotropic glutamate receptors and plasticity are developmentally altered in the CA1 field of Fmr1 knockout mice

Abstract

Fragile X syndrome is one of the most common forms of mental retardation, yet little is known about the physiological mechanisms causing the disease. In this study, we probed the ionotropic glutamate receptor content in synapses of hippocampal CA1 pyramidal neurons in a mouse model for fragile X (Fmr1 KO2). We found that Fmr1 KO2 mice display a significantly lower AMPA to NMDA ratio than wild-type mice at 2 weeks of postnatal development but not at 6-7 weeks of age. This ratio difference at 2 weeks postnatally is caused by down-regulation of the AMPA and up-regulation of the NMDA receptor components. In correlation with these changes, the induction of NMDA receptor-dependent long-term potentiation following a low-frequency pairing protocol is increased in Fmr1 KO2 mice at this developmental stage but not later in maturation. We propose that ionotropic glutamate receptors, as well as potentiation, are altered at a critical time point for hippocampal network development, causing long-term changes. Associated learning and memory deficits would contribute to the fragile X mental retardation phenotype.

Proteomics, Ultrastructure, and Physiology of Hippocampal Synapses in a Fragile X Syndrome Mouse Model Reveal Presynaptic Phenotype

“…Both NMDA and AMPA receptor subunits showed slight small down-regulation in our Fmr1 KO samples, but the changes were not statistically significant. Previous studies reported no overall changes in NMDA and AMPA receptors in the hippocampus of Fmr1 KO1 mice (14,49), but only signaling via an mGluR5-mediated activity-dependent increase in AMPA receptors internalization in Fmr1 KO mice (15,16). Alteration of other signal transduction pathways, especially the decrease in production of cAMP, has been reported in several model systems of FXS (50).…”

“…In the cortex, the absence of FMRP results in reduced long-term potentiation (13,14). In the hippocampus and cere-bellum, enhanced metabotropic glutamate receptor-dependent long-term depression via an increased internalization of membrane-localized AMPA receptors is observed in Fmr1 KO mice (15,16). Activity-dependent changes of synaptic efficacy are encoded by sequential molecular events at the synapse, including FMRP-mediated de novo protein synthesis during the late phase of long-term potentiation and long-term depression (17).…”

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

“…Fmr1 KO2 mice, another Fmr1 null mouse model that lacks both FMRP protein and Fmr1 RNA due to deletion of the Fmr1 promoter and first exon (76), also displays abnormal synaptic plasticity. In the Fmr1 KO2 hippocampus, a lower ratio of AMPA to NMDA receptors was detected early in development compared to wildtype controls (77). The upregulation of NMDA receptors in the Fmr1 KO2 hippocampus resulted in increased NMDA receptor-dependent LTP.…”

Delayed Development of Dendritic Spines in Fxr2 Knockout Mouse

“…We observe here transient aberrations in spine numbers and morphology in the Fxr2 null mice. Transient changes in spines and other synaptic properties have been previously reported in the Fmr1 null mice [19,42]. One question is how such delay in development of spines results in permanent deficits observed in adult mice [12]?…”