Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others


  1. Auerbach, B.D., Osterweil, E.K. & Bear, M.F. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011).

    Article  CAS  Google Scholar 

  2. Michalon, A. et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74, 49–56 (2012).

    Article  CAS  Google Scholar 

  3. Levy, D. et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70, 886–897 (2011).

    Article  CAS  Google Scholar 

  4. Malhotra, D. & Sebat, J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148, 1223–1241 (2012).

    Article  CAS  Google Scholar 

  5. Kumar, R.A. et al. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17, 628–638 (2008).

    Article  CAS  Google Scholar 

  6. Weiss, L.A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008).

    Article  CAS  Google Scholar 

  7. Zufferey, F. et al. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J. Med. Genet. 49, 660–668 (2012).

    Article  CAS  Google Scholar 

  8. Horev, G. et al. Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. Proc. Natl. Acad. Sci. USA 108, 17076–17081 (2011).

    Article  Google Scholar 

  9. Golzio, C. et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 485, 363–367 (2012).

    Article  CAS  Google Scholar 

  10. Portmann, T. et al. Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Reports 7, 1077–1092 (2014).

    Article  CAS  Google Scholar 

  11. Huber, K.M., Gallagher, S.M., Warren, S.T. & Bear, M.F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl. Acad. Sci. USA 99, 7746–7750 (2002).

    Article  CAS  Google Scholar 

  12. Nosyreva, E.D. & Huber, K.M. Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. J. Neurophysiol. 95, 3291–3295 (2006).

    Article  CAS  Google Scholar 

  13. Waung, M.W., Pfeiffer, B.E., Nosyreva, E.D., Ronesi, J.A. & Huber, K.M. Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron 59, 84–97 (2008).

    Article  CAS  Google Scholar 

  14. Jakkamsetti, V. et al. Experience-induced Arc/Arg3.1 primes CA1 pyramidal neurons for metabotropic glutamate receptor-dependent long-term synaptic depression. Neuron 80, 72–79 (2013).

    Article  CAS  Google Scholar 

  15. Wilkerson, J.R. et al. A role for dendritic mGluR5-mediated local translation of Arc/Arg3.1 in MEF2-dependent synapse elimination. Cell Reports 7, 1589–1600 (2014).

    Article  CAS  Google Scholar 

  16. Osterweil, E.K., Krueger, D.D., Reinhold, K. & Bear, M.F. Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J. Neurosci. 30, 15616–15627 (2010).

    Article  CAS  Google Scholar 

  17. Stiedl, O., Palve, M., Radulovic, J., Birkenfeld, K. & Spiess, J. Differential impairment of auditory and contextual fear conditioning by protein synthesis inhibition in C57BL/6N mice. Behav. Neurosci. 113, 496–506 (1999).

    Article  CAS  Google Scholar 

  18. Dölen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007).

    Article  Google Scholar 

  19. Darnell, J.C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).

    Article  CAS  Google Scholar 

  20. Kelleher, R.J. III & Bear, M.F. The autistic neuron: troubled translation? Cell 135, 401–406 (2008).

    Article  CAS  Google Scholar 

Download references


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).

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to Mark F Bear.

Ethics declarations

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.

Supplementary information

Source data

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing