Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine

Abstract

The Ts65Dn mouse is the best-studied animal model for Down syndrome. In the experiments described here, NMDA-mediated or mGluR-mediated LTD was induced in the CA1 region of hippocampal slices from Ts65Dn and euploid control mice by bath application of 20 µM NMDA for 3 min and 50 µM DHPG for 5 min, respectively. We found that Ts65Dn mice display exaggerated NMDA-induced, but not mGluR-induced, LTD in the CA1 region of the hippocampus compared with euploid control animals. In addition, this abnormal level of LTD can be pharmacologically rescued by the NMDA receptor antagonist memantine.

Figure 1.

LTD induced by bath application of either NMDA (5 µM, 3 min) or DHPG (20 µM, 5 min). (A,B) Normalized fEPSP slopes before and after bath application of NMDA. Notice that the hippocampal slices from Ts65Dn mice displayed larger levels of NMDA-induced LTD than those from the euploid control animals, and that preincubation with memantine (1 µM, 4 h) rescued this phenotype. (C,D) Normalized fEPSP slopes before and after bath application of DHPG. Here, the levels of LTD in Ts65Dn mice and euploid control animals are indistinguishable with or without preincubation with memantine. (In A–D, calibration bars represent 1 mV and 10 msec.) (E) Summary graph representation of the ANOVA of the LTD data (mean fEPSP depression ± SEM; with fEPSP depression = the average baseline fEPSP slope—average fEPSP slope during the last 10 min of recording for each hippocampus slice) in A and C showing which differences reached significance in the post hoc analyses. (F) Summary graph representation of the ANOVA of the LTD data (mean ± SEM) in B and D. Statistical significance is expressed in this figure: (**) P < 0.01.

Figure 2.

Preincubation with memantine had no significant effect on basal synaptic transmission in slices from either euploid control or Ts65Dn mice. (A) Input–output function at the CA3–CA1 hippocampal synapse for untreated euploid control and Ts65Dn hippocampal slices and control, and Ts65Dn slices pre-incubated with memantine. Input intensities were set at 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 µA. Repeated measures ANOVA showed no significant group effect. (B) Paired-pulse facilitation was assessed at 11 different interpulse intervals: 25, 50, 75, 100, 125, 150, 175, 200, 300, 400, and 500 msec in the four groups of slices (i.e., untreated control, untreated Ts65Dn, control preincubated with memantine, and Ts65Dn preincubated with memantine). Again, repeated measures ANOVA failed to reveal a significant group effect. (n = 12 for each group in all experiments.)

Figure 3.

Flowchart describing how different genetic insults (trisomy 21 or FMR1 gene mutation) can produce functionally similar phenotypes (exaggerated LTD) through unrelated, parallel mechanisms.