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Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion

Nature Neuroscience volume 18, pages 182–184 (2015)Cite this article

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Abstract

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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Figure 1: mGluR-LTD is protein synthesis independent in 16p11.2 df/+ mice.
Figure 2: 16p11.2 df/+ mice exhibit deficits in hippocampal-associated CFC and IA.
Figure 3: 16p11.2 df/+ mice exhibit a decrease in basal protein synthesis which is accompanied by an increase in Arc protein levels.

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Acknowledgements

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).

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge,, Massachusetts, USA

    Di Tian, Laura J Stoppel, Arnold J Heynen & Mark F Bear

  2. The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge,, Massachusetts, USA

    Di Tian, Laura J Stoppel, Arnold J Heynen & Mark F Bear

  3. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge,, Massachusetts, USA

    Di Tian, Laura J Stoppel, Arnold J Heynen & Mark F Bear

  4. Department of Pathology and Laboratory Medicine, Developmental Neuroscience Program, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

    Di Tian

  5. Pharmaceuticals Division, F. Hoffmann-La Roche, Basel, Switzerland

    Lothar Lindemann & Georg Jaeschke

  6. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA

    Alea A Mills

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  1. Di Tian
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Contributions

M.F.B. and D.T. conceived and designed the study. M.F.B. and A.J.H. supervised the study. D.T. performed hippocampal electrophysiology and contextual fear conditioning. D.T. and A.J.H. performed inhibitory avoidance test. L.J.S. performed hippocampal protein synthesis and immunoblot experiments. D.T., A.J.H., L.J.S. and M.F.B. wrote the manuscript. L.L. and G.J. provided CTEP. A.A.M. provided the 16p11.2 df/– mice before publication and edited the manuscript.

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Correspondence to Mark F Bear.

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Competing interests

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

Supplementary Figure 1 Steady decline of transmission rate of the 16p11.2 df/+ allele.

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.

Supplementary Figure 2 Basal synaptic transmission is normal in the 16p11.2 df/+ mice.

(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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