Altered synaptic plasticity in a mouse model of fragile X mental retardation

Abstract

Fragile X syndrome, the most common inherited form of human mental retardation, is caused by mutations of the Fmr1 gene that encodes the fragile X mental retardation protein (FMRP). Biochemical evidence indicates that FMRP binds a subset of mRNAs and acts as a regulator of translation. However, the consequences of FMRP loss on neuronal function in mammals remain unknown. Here we show that a form of protein synthesis-dependent synaptic plasticity, long-term depression triggered by activation of metabotropic glutamate receptors, is selectively enhanced in the hippocampus of mutant mice lacking FMRP. This finding indicates that FMRP plays an important functional role in regulating activity-dependent synaptic plasticity in the brain and suggests new therapeutic approaches for fragile X syndrome.

Figure 1

Synaptic induction of mGluR-LTD using PP-LFS is significantly enhanced in hippocampus of Fmr1-KO mice as compared with WT controls. (A1) Average time course of the change in FPs after PP-LFS. LTD in KO animals measured 82 ± 3% of prePP-LFS baseline (n = 18 slices from 8 mice; open circles) as compared with 93 ± 2% in WT controls (n = 21 slices from 10 mice; filled circles; different at P = 0.004, t test). (A2) Representative FPs (2 min average) taken at the times indicated by the numbers on the graph. [Bars = 1 mV, 5 msec (1, 2) and 1 mV, 10 msec (PP-LFS).] (B) Cumulative probability distributions of FP slope values (% of baseline), measured 1 h after PP-LFS in individual slices from both KO and WT groups. The distribution in KO mice is significantly different from that in WT mice, as determined by Kolmolgarov–Smirnov test (P < 0.05). All experiments were performed blind, in the presence of the NMDAR antagonist D-APV (50 μM).

Figure 2

Brief application of the mGluR agonist DHPG (5 min; 100 μM) induces greater LTD of synaptic responses in hippocampus of Fmr1-KO mice as compared with WT littermate controls. (A1) Plotted are average (±SEM) FP slope values over the time course of the experiment. In Fmr1-KO animals, the response 60 min after treatment was depressed to 77 ± 3% of preDHPG baseline (n = 21 slices from 9 mice; open circles); in interleaved WT controls, the response was depressed to 88 ± 4% of baseline (n = 15 slices from 8 mice; filled circles; different at P = 0.02; t test). (A2) Representative FPs (2 min average) taken at the times indicated by the numbers on the graph. (Bar = 1 mV; 5 msec.) (B) Cumulative probability distributions of FP slope values (% of baseline), measured 1 h after DHPG in individual slices from both KO and WT groups. The distribution in KO mice is significantly different from that in WT mice as determined by Kolmolgarov–Smirnov test (P < 0.05).

Figure 3

Synaptic induction of NMDAR-dependent LTD using a 1-Hz LFS protocol is comparable in Fmr1-KO mice and WT controls. (A1) Average time course of the change in FPs after LFS. LTD in KO animals measured 86 ± 4% of preLFS baseline (n = 14 slices from 8 mice; open circles) as compared with 84 ± 4% in WT controls (n = 12 slices from 4 mice; filled circles; P = 0.6, t test). (A2) Representative FPs (2 min average) taken at the times indicated by the numbers on the graph. (Bar = 1 mV, 10 msec.) (B) Cumulative probability distributions of FP slope values (% of baseline), measured 1 h after LFS in individual slices from both KO and WT groups. The distribution in KO mice is not significantly different from that in WT mice as determined by the Kolmolgarov–Smirnov test. All experiments were performed blind.

Figure 4

Model. Previous research has shown that activation of mGluR5 stimulates the internalization of AMPA receptors and NMDARs (not shown; ref. 11). The stable expression of this modification requires protein synthesis, which we propose is negatively regulated by FMRP synthesized in response to mGluR activation. Therefore, in the absence of FMRP, LTD magnitude is increased.