Article | Published:

Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin

Nature Medicine volume 15, pages 14071413 (2009) | Download Citation


Huntington's disease is caused by an expanded CAG repeat in the gene encoding huntingtin (HTT), resulting in loss of striatal and cortical neurons. Given that the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here we show the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt) and neuronal survival. Synaptic N-methyl-D-aspartate–type glutamate receptor (NMDAR) activity induces mtHtt inclusions via a T complex-1 (TCP-1) ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases the vulnerability of mtHtt-containing neurons to cell death by impairing the neuroprotective cyclic AMP response element–binding protein (CREB)–peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) cascade and increasing the level of the small guanine nucleotide–binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic mice expressing a yeast artificial chromosome containing 128 CAG repeats (YAC128) with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine, which blocks both extrasynaptic and synaptic NMDAR activity, decreases neuronal inclusions and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in Huntington's disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).

  2. 2.

    et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).

  3. 3.

    & The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40, 427–446 (2003).

  4. 4.

    et al. Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. Nature 321, 168–171 (1986).

  5. 5.

    et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J. Neurosci. 22, 1592–1599 (2002).

  6. 6.

    et al. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 33, 849–860 (2002).

  7. 7.

    , , , & In vivo evidence for NMDA receptor–mediated excitotoxicity in a murine genetic model of Huntington disease. J. Neurosci. 29, 3200–3205 (2009).

  8. 8.

    et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum. Mol. Genet. 12, 1555–1567 (2003).

  9. 9.

    Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat. Rev. Drug Discov. 5, 160–170 (2006).

  10. 10.

    Pathologically activated therapeutics for neuroprotection. Nat. Rev. Neurosci. 8, 803–808 (2007).

  11. 11.

    , & Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414 (2002).

  12. 12.

    , , & Enhanced striatal NR2B-containing N-methyl-D-aspartate receptor–mediated synaptic currents in a mouse model of Huntington disease. J. Neurophysiol. 92, 2738–2746 (2004).

  13. 13.

    Folding away the bad guys. Nat. Rev. Neurosci. 7, 832–833 (2006).

  14. 14.

    , , & The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions. Nat. Cell Biol. 8, 1155–1162 (2006).

  15. 15.

    , , , & The Hsp70 and TRiC/CCT chaperone systems cooperate in vivo to assemble the von Hippel-Lindau tumor suppressor complex. Mol. Cell. Biol. 23, 3141–3151 (2003).

  16. 16.

    et al. TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. Mol. Cell 23, 887–897 (2006).

  17. 17.

    et al. Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state. Nat. Cell Biol. 8, 1163–1170 (2006).

  18. 18.

    et al. Cytoplasmic inclusions of Htt exon1 containing an expanded polyglutamine tract suppress execution of apoptosis in sympathetic neurons. J. Neurosci. 28, 14401–14415 (2008).

  19. 19.

    et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548 (1997).

  20. 20.

    , , & Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).

  21. 21.

    , , & Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat. Neurosci. 7, 1181–1183 (2004).

  22. 22.

    , , , & Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805–810 (2004).

  23. 23.

    , & Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373–379 (2003).

  24. 24.

    Apoptosis and caspases in neurodegenerative diseases. N. Engl. J. Med. 348, 1365–1375 (2003).

  25. 25.

    & The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J. Neurosci. 19, 4180–4188 (1999).

  26. 26.

    & Excitatory amino acids as a final common pathway for neurologic disorders. N. Engl. J. Med. 330, 613–622 (1994).

  27. 27.

    et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43, 729–743 (2004).

  28. 28.

    et al. An astrocytic basis of epilepsy. Nat. Med. 11, 973–981 (2005).

  29. 29.

    , , & Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324, 1327–1330 (2009).

  30. 30.

    et al. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291, 2423–2428 (2001).

  31. 31.

    & PGC-1α, a new therapeutic target in Huntington's disease? Cell 127, 465–468 (2006).

  32. 32.

    et al. Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J. Neurosci. 12, 4427–4436 (1992).

  33. 33.

    , , & Brain penetration and in vivo recovery of NMDA receptor antagonists amantadine and memantine: a quantitative microdialysis study. Pharm. Res. 16, 637–642 (1999).

  34. 34.

    , & Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system—too little activation is bad, too much is even worse. Neuropharmacology 53, 699–723 (2007).

  35. 35.

    et al. Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J. Neurosci. 19, 2522–2534 (1999).

  36. 36.

    et al. Neuropathological classification of Huntington's disease. J. Neuropathol. Exp. Neurol. 44, 559–577 (1985).

  37. 37.

    et al. Transcriptional repression of PGC-1α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127, 59–69 (2006).

  38. 38.

    , , , & Nuclear Ca2+ and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection. J. Neurosci. 25, 4279–4287 (2005).

  39. 39.

    et al. Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability. J. Neurosci. 26, 4509–4518 (2006).

  40. 40.

    et al. The N-methyl-D-aspartate antagonist memantine retards progression of Huntington's disease. J. Neural Transm. Suppl. 68, 117–122 (2004).

  41. 41.

    et al. Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis. Proc. Natl. Acad. Sci. USA 99, 3974–3979 (2002).

  42. 42.

    et al. Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex. Neuron 8, 1087–1099 (1992).

  43. 43.

    et al. Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington's disease. J. Neurosci. 25, 4169–4180 (2005).

Download references


We thank C.A. Ross (Johns Hopkins University School of Medicine) and L.M. Ellerby (Buck Institute for Age Research) for N-terminal and full-length constructs of huntingtin, T.F. Newmeyer and H. Fang (Burnham Institute for Medical Research) for preparing primary neuronal cultures, X.-J. Li (Emory University School of Medicine) for providing the EM48 antibody and E. Bossy-Wetzel, Y.S. Choo, W. Zago and T. Nakamura for assistance or discussion. This work was supported in part by US National Institutes of Health grants P01 HD29587, P01 ES016738, R01 EY09024, R01 EY05477 and R01 NS41207 and a Senior Scholar Award in Aging Research from the Ellison Medical Foundation (S.A.L.). Additional support was provided by the National Institutes of Health Blueprint Grant for La Jolla Interdisciplinary Neuroscience Center Cores P30 NS057096. M.A.P. was supported by the Canadian Institute of Health Research and the Michael Smith Foundation for Health Research. M.R.H. was supported by grants from the Canadian Institutes of Health Research, the Huntington Society of Canada, the Huntington's Disease Society of America, CHDI Foundation, Inc., and the HighQ Foundation.

Author information

Author notes

    • Shu-ichi Okamoto
    • , Mahmoud A Pouladi
    • , Maria Talantova
    •  & Dongdong Yao

    These authors contributed equally to this work.


  1. Center for Neuroscience, Aging and Stem Cell Research, Burnham Institute for Medical Research, La Jolla, California, USA.

    • Shu-ichi Okamoto
    • , Maria Talantova
    • , Dongdong Yao
    • , Peng Xia
    • , Rameez Zaidi
    • , Arjay Clemente
    • , Marcus Kaul
    • , Dongxian Zhang
    • , H-S Vincent Chen
    • , Gary Tong
    •  & Stuart A Lipton
  2. Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.

    • Mahmoud A Pouladi
    • , Dagmar E Ehrnhoefer
    • , Rona K Graham
    •  & Michael R Hayden
  3. Division of Cardiology, University of California at San Diego, La Jolla, California, USA.

    • H-S Vincent Chen
  4. Department of Neurosciences, University of California at San Diego, La Jolla, California, USA.

    • Gary Tong
    •  & Stuart A Lipton


  1. Search for Shu-ichi Okamoto in:

  2. Search for Mahmoud A Pouladi in:

  3. Search for Maria Talantova in:

  4. Search for Dongdong Yao in:

  5. Search for Peng Xia in:

  6. Search for Dagmar E Ehrnhoefer in:

  7. Search for Rameez Zaidi in:

  8. Search for Arjay Clemente in:

  9. Search for Marcus Kaul in:

  10. Search for Rona K Graham in:

  11. Search for Dongxian Zhang in:

  12. Search for H-S Vincent Chen in:

  13. Search for Gary Tong in:

  14. Search for Michael R Hayden in:

  15. Search for Stuart A Lipton in:


S.-i.O. and D.Y. designed and performed the in vitro experiments. R.Z. and A.C. assisted with the in vitro experiments. M.K. offered key advice and helped analyze the in vitro experiments on mtHtt inclusions and cell death. M.A.P., D.E.E. and R.K.G. designed and conducted the mouse studies. M.R.H. conceptualized and supervised the mouse studies. M.T. and P.X. performed the electrophysiology experiments. D.Z., H.-S.V.C., G.T. and S.A.L. supervised the electrophysiological experiments and gave crucial advice. S.-i.O., M.A.P., M.T., D.Y. and M.R.H. wrote the first draft of the manuscript. S.-i.O. and S.A.L. formulated the hypothesis, conceptualized the entire study and wrote the manuscript.

Competing interests

S.L. is the named inventor on numerous patents in territories worldwide for the use of memantine in neurodegenerative disorders. He has no direct ownership in the drug, which is currently clinically approved and marketed for moderate to severe Alzheimer’s disease under the name Namenda. Under the rules of Harvard University, his former institution where the work was initially performed, S.L. participates in a royalty-sharing plan administered by Harvard Medical School and Children’s Hospital, Boston.

Corresponding authors

Correspondence to Michael R Hayden or Stuart A Lipton.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–18 and Supplementary Methods

About this article

Publication history





Further reading