29 Jan 2010

NMDA receptors populate the synapse, where they participate in nerve signaling and promote cell survival pathways. But those same receptors, when they spread out into extrasynaptic regions, can activate apoptosis. In the January 28 Neuron, researchers from the University of British Columbia in Vancouver, Canada, report that neurons from a mouse model of Huntington disease (HD) have more of these dangerous extrasynaptic NMDA receptors. The report comes on the heels of a paper in December’s Nature Medicine, led by scientists at the Burnham Institute in La Jolla, California, showing that synaptic NMDA receptors promote the formation of inclusions that sequester the toxic huntingtin in the same model. Both groups report data suggesting that low doses of memantine, which blocks extrasynaptic receptors, could treat HD.

NMDA receptors are cation channels that open in response to the neurotransmitter glutamate. Synaptic receptors turn on protective mechanisms such as the PI3K-Akt and CREB pathways. In contrast, the function of extrasynaptic receptors is uncertain; they may serve as a reserve pool that is able to quickly enter the synapse if needed. However, these extrasynaptic receptors can cause mischief. When opened, they can let in excess calcium, inducing mitochondrial dysfunction and other stress pathways that may lead to cell death. Scientists have attempted to block the pro-apoptotic activity of NMDA receptors in stroke treatments, but with little success, possibly because the treatment also interferes with pro-survival pathways. In animal studies, activation of NMDA receptors before ischemia actually appears to be protective (reviewed in Papadia and Hardingham, 2007).

In the Neuron paper, first author Austen Milnerwood, principal investigator Lynn Raymond, and colleagues used patch-clamp recordings to study the NMDA receptor response in brain slices from mice expressing human huntingtin with either 18 CAG repeats, a normal amount, or 128 repeats, a pathogenic form. Spontaneous firing was limited to synaptic NMDA receptors, and was not affected by pathogenic huntingtin. The researchers stimulated the neurons to induce a signal that would open not only the synaptic receptors, but spill over into the extrasynaptic area as well. Under those conditions, the slices with the Htt-128 showed increased current.

The extrasynaptic receptors with pathogenic huntingtin could be more sensitive to activation, or there could simply be more of them. The researchers investigated this question by fractionating synaptosomes from the slices. They separated synaptosomes into an insoluble fraction containing the post-synaptic portion of the membrane and a soluble fraction containing the presynaptic and extrasynaptic membranes. There were more NMDA receptor subunits in the soluble fraction from Htt-128 mice than from Htt-18 mice. “Mutant huntingtin expression leads to increased numbers of NMDA receptors outside synapses,” Raymond concluded. “That would be predicted to produce detrimental signaling for the cell.”

The Neuron paper suggests that pathogenic huntingtin influences NMDA receptor localization and activity. In the Nature Medicine paper, which shared some of the same authors, the researchers report that NMDA receptors influence huntingtin aggregation. This work was led by joint first authors Shu-ichi Okamoto, Maria Talantova, and Dongdong Yao of the Burnham Institute and Mahmoud Pouladi of the University of British Columbia, with principal investigators Michael Hayden of the University of British Columbia and Stuart Lipton at the Burnham Institute. In primary neuronal cultures, these scientists found that synaptic NMDA receptors promoted the aggregation of pathogenic huntingtin, sequestering the protein in inclusions where they inflicted less damage on the cells. Stimulation of extrasynaptic receptors, in contrast, impaired the protective CREB pathway, increased signals known to promote huntingtin disaggregation, and promoted cell death.

Combined, the two papers describe a feedback loop in which mutant huntingtin promotes extrasynaptic NMDA receptor localization and activation, which in turn reduce huntingtin aggregation and promote cell death. Therefore, a therapeutic aimed at these pathways should specifically block extrasynaptic receptors and leave the synaptic ones open.

Memantine, in low doses, blocks only extrasynaptic NMDA receptors; in high doses, it blocks all receptors. Both papers report that low-dose memantine (1 mg/kg body weight) was protective in HD model mice. In the Nature Medicine report, the researchers showed that treated mice had increased inclusion formation, increased striatal volume, and improved performance on a rotarod test. A higher dose of the drug worsened symptoms. In the Neuron paper, the authors reported that the same low dose of memantine augmented CREB signaling and improved motor learning skills in HD model mice.

“There is a whole story beginning here,” said Michael Levine of UCLA, who wrote a preview accompanying the Neuron paper. “They put together a number of observations.” The current data make a convincing case that the Alzheimer disease drug memantine, which has been tried in a small handful of people with Huntington disease (Ondo et al., 2007), warrants further investigation in a large, carefully controlled trial for HD, he said. Beyond that, NMDA receptor dichotomy could be pursued in other neurodegenerative diseases. In AD, the effect of memantine specifically on extrasynaptic NMDA receptors has drawn some scrutiny already (Zhao et al., 2007).—Amber Dance

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References

Paper Citations

1. Papadia S, Hardingham GE. The dichotomy of NMDA receptor signaling. Neuroscientist. 2007 Dec;13(6):572-9. PubMed.
2. Ondo WG, Mejia NI, Hunter CB. A pilot study of the clinical efficacy and safety of memantine for Huntington's disease. Parkinsonism Relat Disord. 2007 Oct;13(7):453-4. PubMed.
3. Zhao X, Marszalec W, Toth PT, Huang J, Yeh JZ, Narahashi T. In vitro galantamine-memantine co-application: mechanism of beneficial action. Neuropharmacology. 2006 Dec;51(7-8):1181-91. PubMed.

Further Reading

Papers

1. Alberdi E, Sánchez-Gómez MV, Cavaliere F, Pérez-Samartín A, Zugaza JL, Trullas R, Domercq M, Matute C. Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium. 2010 Mar;47(3):264-72. PubMed.
2. Cowan CM, Fan MM, Fan J, Shehadeh J, Zhang LY, Graham RK, Hayden MR, Raymond LA. Polyglutamine-modulated striatal calpain activity in YAC transgenic huntington disease mouse model: impact on NMDA receptor function and toxicity. J Neurosci. 2008 Nov 26;28(48):12725-35. PubMed.
3. Torres-Peraza JF, Giralt A, García-Martínez JM, Pedrosa E, Canals JM, Alberch J. Disruption of striatal glutamatergic transmission induced by mutant huntingtin involves remodeling of both postsynaptic density and NMDA receptor signaling. Neurobiol Dis. 2008 Mar;29(3):409-21. PubMed.
4. Petralia RS, Wang YX, Hua F, Yi Z, Zhou A, Ge L, Stephenson FA, Wenthold RJ. Organization of NMDA receptors at extrasynaptic locations. Neuroscience. 2010 Apr 28;167(1):68-87. PubMed.
5. Boon WC, van den Buuse M, Wegener N, Martin S, Chua HK, Bush AI, Masters CL, Adlard PA, Li QX. Behavioural phenotype of APPC100.V717F transgenic mice over-expressing a mutant Abeta-bearing fragment is associated with reduced NMDA receptor density. Behav Brain Res. 2010 May 1;209(1):27-35. PubMed.
6. Hu NW, Klyubin I, Anwyl R, Anwy R, Rowan MJ. GluN2B subunit-containing NMDA receptor antagonists prevent Abeta-mediated synaptic plasticity disruption in vivo. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20504-9. PubMed.
7. Fan MM, Fernandes HB, Zhang LY, Hayden MR, Raymond LA. Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington's disease. J Neurosci. 2007 Apr 4;27(14):3768-79. PubMed.

News

1. Reelin, Aβ, α7 Play Yin and Yang Around NMDA Receptors 4 Sep 2009
2. Memantine—Good for a Year, But Little Disease Modification 12 Jan 2006
3. Chew the Fat—Lipids, NMDARs Mediate Neuronal Response to Aβ 22 Nov 2009
4. Aβ Oligomers and NMDA Receptors—One Target, Two Toxicities 15 Mar 2007
5. NMDA Receptor Activation and Aβ Oligomer Toxicity 8 Aug 2006
6. Memantine Wins FDA Approval 21 Oct 2003