Human chromosome 16p11.2 microdeletion is the most common gene copy number variation in autism, but the synaptic pathophysiology caused by this mutation is largely unknown. Using a mouse with the same genetic deficiency, we found that metabotropic glutamate receptor 5 (mGluR5)-dependent synaptic plasticity and protein synthesis was altered in the hippocampus and that hippocampus-dependent memory was impaired. Notably, chronic treatment with a negative allosteric modulator of mGluR5 reversed the cognitive deficit.
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We thank B. Auerbach, E. Sklar and S. Meagher for technical and administrative assistance. This work was partly supported by grants and funding to M.B. from the National Institute of Mental Health (R21MH090452), NICHD (R01HD046943), Simons Foundation (SFARI #240559) and the Simons Center for the Social Brain at the Massachusetts Institute of Technology, and a physician-scientist career development award from the National Institute of Child Health and Human Development (5K08HD053824) to D.T. L.J.S. was supported by National Institute of Mental Health training grant (5T32MH074249).
M.F.B. holds patents on the use of mGluR5 inhibitors for treatment of fragile X and autism. M.F.B. and D.T. have patents pending on use of mGluR5 inhibitors for treatment of 16p11.2 microdeletion. L.L. and G.J. are employees of Roche Pharmaceuticals.
Integrated supplementary information
The percentage of the heterozygous 16p11.2 df/+ mutant mice, including both male and female, gradually declines across multiple generations during backcrossing to C57BL/6J. The number of 16p11.2 df/+ and total mice for each generation are: N5: 21/53, N6: 26/118, N7: 41/250, N8: 57/434, N9: 16/202, and N10: 8/102.
(a) Input-output functions, plotted as fEPSP slope versus stimulus intensity, are not different between the WT (n = 14 animals) and mutant mice (n = 14 animals). Repeated measures one-way ANOVA, p = 0.92.
(b) Paired-pulse facilitation is comparable between the WT (n = 16 animals) and mutant (n = 17 animals) mice across multiple stimulus intervals (10, 20, 50, 100, 200, 300, 500 ms). Repeated measures one-way ANOVA, p = 0.76. All data are plotted as mean ± SEM.
Supplementary Figure 3 Presynaptic LTD is independent of genotype and is not affected by cycloheximide treatment.
DHPG increases paired-pulse facilitation in both the WT and 16p11.2 df/+ mutant slices and this effect is not affected by cycloheximide. PPF is calculated at a 50 ms inter-stimulus interval: WT baseline: 1.44 ± 0.019, n = 17 animals, 37 slices, WT DHPG: 1.55 ± 0.035, n = 17 animals, 18 slices, WT DHPG+CHX: 1.55 ± 0.027, n = 17 animals, 19 slices. Mut baseline: 1.45 ± 0.023, n = 16 animals, 42 slices, Mut DHPG:1.56 ± 0.053, n = 16 animals, 21 slices, Mut DHPG+CHX: 1.53 ± 0.038, n = 16 animals, 21 slices. Statistical analyses are performed using unpaired t-tests. All data are plotted as mean ± SEM.
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Tian, D., Stoppel, L., Heynen, A. et al. Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion. Nat Neurosci 18, 182–184 (2015). https://doi.org/10.1038/nn.3911
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