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).
Milnerwood AJ, Gladding CM, Pouladi MA, Kaufman AM, Hines RM, Boyd JD, Ko RWY, Vasuta OC, Graham RK, Hayden MR, Murthy TH, Raymond LA. Early increase in extrasynaptic NMDA receptor onset in Huntington’s disease mice. Neuron. 2010 Jan 28; 65:178-90.
Levine MS, Cepeda C, Andr VM. Location, location, location: Contrasting roles of synaptic and extrasynaptic NMDA receptors in Huntington’s disease. Neuron. 2010 Jan 28; 65:145-7.
Okamoto S, Pouladi MA, Talatova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Vincent Chen HS, Tong G, Hayden MR, Lipton SA. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med. 2009 Dec; 15(12):1407-13. Abstract
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