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

Abstract

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.

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Figure 1: Suppression of excitatory NMDAR synaptic transmission ameliorates inclusion formation in mtHtt-expressing neurons.
Figure 2: Pharmacology of NMDAR-mediated sEPSCs and whole-cell currents recorded from wtHtt- and mtHtt-transfected neurons.
Figure 3: Involvement of the chaperonin TRiC TCP-1 subunit in synaptic activity–mediated inclusion formation.
Figure 4: Effect of excitatory synaptic versus extrasynaptic activity in Huntington's disease–related neuronal cell death.
Figure 5: Long-term treatment with memantine affects neuropathology and motor function in a dose-specific manner in transgenic YAC128 mice.
Figure 6: Schematic model showing the role of physiological synaptic versus excessive extrasynaptic NMDAR activity in the neurodegeneration of Huntington's disease.

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Acknowledgements

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.

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Contributions

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.

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Correspondence to Michael R Hayden or Stuart A Lipton.

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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.

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Okamoto, Si., Pouladi, M., Talantova, M. et al. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 15, 1407–1413 (2009). https://doi.org/10.1038/nm.2056

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