Studies Challenge Model of NMDA Receptor Function

Glutamate receptors at the postsynaptic membrane play important roles in neural plasticity. It is widely accepted that they either strengthen or weaken neurotransmission by allowing an influx of positively charged ions into the cell. But hold on. Two papers in the February 19 PNAS online suggest otherwise. Researchers led by Roberto Malinow at the University of California, San Diego, propose that NMDA-type glutamate receptors (NMDARs) weaken synaptic transmission via an indirect, metabotropic mechanism. Furthermore, the researchers trace Aβ toxicity to this same metabotropic action. The findings challenge a long-held view of synaptic plasticity and suggest a possible therapeutic target for Alzheimer’s disease.

“We thought we knew most of the ins and outs of how the NMDA receptor worked,” Malinow told Alzforum. “These findings are changing a model that has been in textbooks for 20 years.”

The model posits that lots of calcium influx into a postsynaptic neuron leads to long-term potentiation—a strengthening of synapses by addition of AMPA receptors. A smidgen of calcium influx would cause receptor removal and long-term depression (LTD). Malinow and colleagues wanted to put that hypothesis to the test.

Previous work established that LTD can be prevented by using chelators to sequester calcium in postsynaptic neurons (see Bröcher et al., 1992, and Cho et al., 2001). However, when Sadegh Nabavi and colleagues blocked ion flow through NMDA receptors with channel blockers MK-801 and 7-chlorokynurenate, a low-frequency stimulus still resulted in LTD. In contrast, D-APV, an antagonist of glutamate binding to the GluN2 subunit of the NMDA receptor, prevented LTD. The findings indicated that NMDA receptors can depress synaptic transmission without conducting calcium.

The authors propose that the receptors instead work metabotropically, i.e., by conformational change. Activation of the signaling molecule p38 MAP kinase has previously been implicated in LTD, for example (see Zhu et al., 2002), and Nabavi found that D-APV, but not MK-801, blocked an NMDA-induced increase in p38 MAPK phosphorylation, suggesting this might be the trigger for LTD.

These results seem to be at odds with calcium chelators blocking LTD. The authors hypothesized that those compounds suppress LTD by targeting calcium already in the cell, rather than preventing calcium influx through NMDA receptors. To test that, they added the chelator BAPTA to neurons while adding extra calcium into the cell to raise basal ion levels back to normal. In this scenario, BAPTA buffered incoming calcium but left LTD untouched, supporting the premise that synaptic depression occurs without calcium influx. Intracellular calcium is necessary for LTD because it maintains some crucial signaling pathways, suggested the authors.

Some researchers remain unconvinced. Robert Malenka, Stanford University, California, noted that methods of measuring calcium changes are too insensitive to detect trace amounts of ion flow. “Even a trickle of calcium through those receptors could rule out the hypothesis that calcium entry through the NMDA receptor is unnecessary,” he told Alzforum. If LTD can be induced independently of calcium, then the mechanism probably coexists with a calcium-dependent mechanism, he said. Malenka previously showed that activation of calcium channels alone led to LTD (see Cummings et al., 1996).

How does this new view of LTD fit with Aβ, which drives LTD? This is where it gets more complicated. In their second paper, Malinow’s group argues that Aβ also works by metabotropic NMDAR activation. Previously, the scientists showed that Aβ induced LTD, but the underlying signaling pathways were unclear (see ARF related news story on Hsieh et al., 2006). They wanted to probe further.

Using a viral vector, first author Helmut Kessels overproduced Aβ in rat hippocampal neurons. AMPA transmission fell, but was restored by scyllo-inositol, which prevents formation of Aβ oligomers. The NMDA channel blockers MK-801 and ketamine had no effect on this depression, but a GluN2 antagonist relieved it. Together, these findings suggest that ion flow is unnecessary for Aβ oligomer-driven LTD, the authors claim.

Since blockage of NMDARs containing the GluN2B subunit has been shown to prevent Aβ-induced depression (see ARF related news story on Hu et al., 2009), the researchers wanted to know if Aβ-induced depression depended on GluN2 receptor subtype. They found that general GluN2 antagonists reduced that synaptic depression somewhat, but GluN2B-specific antagonists almost completely abolished it, suggesting Aβ acts mainly on GluN2B subunits.

“The papers are interesting and reasonably convincing,” wrote Graham Collingridge, University of Bristol, U.K. He agrees that while scientists have assumed LTD requires calcium influx, previous observations could be explained by a need for basal calcium only. “I wouldn't want to completely discard the idea that calcium has to rise based on these results alone, though.” The results will likely prompt others to study the mechanisms involved, he wrote.

Other experts were skeptical that Aβ works independently of ion channels. Some researchers asked how that fits with numerous reports of the NMDA antagonist memantine reversing Aβ deficits. Researchers suggested checking to see if this approved Alzheimer’s drug can prevent Aβ-driven LTD.

The idea that Aβ could modify NMDARs metabotropically is plausible, said Malenka. “It’s an important hypothesis that the field needs to pursue in a vigorous way,” he told Alzforum. “If true, it says that if a compound can interfere with binding of the modulatory ligand to the NMDA receptor, that would be a potential valuable therapeutic agent.”—Gwyneth Dickey Zakaib

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References

News Citations

  1. AMPA Receptors: Going, Going, Gone in Aβ-exposed Synapses, PSD95 Knockouts
  2. Chew the Fat—Lipids, NMDARs Mediate Neuronal Response to Aβ

Paper Citations

  1. Bröcher S, Artola A, Singer W. Intracellular injection of Ca2+ chelators blocks induction of long-term depression in rat visual cortex. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):123-7. PubMed.
  2. Cho K, Aggleton JP, Brown MW, Bashir ZI. An experimental test of the role of postsynaptic calcium levels in determining synaptic strength using perirhinal cortex of rat. J Physiol. 2001 Apr 15;532(Pt 2):459-66. PubMed.
  4. Cummings JA, Mulkey RM, Nicoll RA, Malenka RC. Ca2+ signaling requirements for long-term depression in the hippocampus. Neuron. 1996 Apr;16(4):825-33. PubMed.
  5. Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron. 2006 Dec 7;52(5):831-43. 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.

Further Reading

Papers

  1. Limapichat W, Yu WY, Branigan E, Lester HA, Dougherty DA. Key Binding Interactions for Memantine in the NMDA Receptor. ACS Chem Neurosci. 2013 Feb 20;4(2):255-60. PubMed.
  2. Santangelo RM, Acker TM, Zimmerman SS, Katzman BM, Strong KL, Traynelis SF, Liotta DC. Novel NMDA receptor modulators: an update. Expert Opin Ther Pat. 2012 Nov;22(11):1337-52. PubMed.

Primary Papers

  1. Nabavi S, Kessels HW, Alfonso S, Aow J, Fox R, Malinow R. Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression. Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4027-32. PubMed.
  2. Kessels HW, Nabavi S, Malinow R. Metabotropic NMDA receptor function is required for β-amyloid-induced synaptic depression. Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4033-8. PubMed.

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