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Rethinking Learning and Memory—mGluRs, LTP, and Potential Therapies

17 January 2008. Long-term potentiation (LTP), or the ability of neurons to ramp up activity in response to increasing stimulation, is an important facet of neuronal plasticity and is essential for learning, memory, and cognition. Though LTP driven by NMDA-type glutamate receptors is one the most important and well-studied forms of synaptic plasticity, it is not without its foibles—in some experimental models, NMDA-driven LTP soon plateaus, which would suggest limitations on learning. In the January 4 Science, researchers describe a biological mechanism that compensates for this saturation. Alison Barth and colleagues at Carnegie Mellon University, Pittsburgh, Pennsylvania, report that not only does NMDA-driven LTP reach saturation upon sensory stimulation, but that NMDA activation eventually depresses LTP. When that happens, metabotropic glutamate receptors (mGluRs) appear to drive LTP instead. The finding offers a new twist on the biology underlying learning and memory and may offer new insight into cognitive dysfunction found in a variety of diseases, including schizophrenia. A Science perspective by Michael Brecht and Dietmar Schmitz at the Humboldt-University, Berlin, Germany, offers more insight into how this finding relates to what we know about synaptic plasticity.

The researchers found the link between mGluR activation and LTP when studying sensory learning in mice. The researchers capitalized on a well-known phenomenon whereby barrel-shaped columns of neurons in the sensory cortex are activated upon stimulation of specific facial whiskers. Barth has developed a line of transgenic mice in which barrel cortex neurons express green fluorescent protein (GFP) driven by the c-fos promoter. Because c-fos is turned on when neurons are activated, the researchers can identify exactly which column of neurons respond when a whisker is tweaked. With this paradigm the researchers were able to correlate electrical activity in the column of fluorescing neurons with sensory stimulation. The researchers removed all but one whisker to keep things simple.

First author Roger Clem and colleagues found that a “single whisker experience,” or SWE, leads to enhanced synaptic activity when the corresponding column of neurons was tested in vitro. This LTP is blocked, however, if the animal is treated first with an NMDA antagonist, CPP (carboxypiperazin-4-yl-propyl—1-phosphonic acid), which is in keeping with the role of NMDA receptors in synaptic potentiation. To test if the NMDA-driven LTP could be saturated, the researchers tried a second bout of SWE treatment 24 hours after the first. Interestingly, this not only failed to elicit further LTP, but actually depressed synaptic activity. “This was totally unexpected,” said Barth. “We know that NMDA receptors are important for potentiation, but to see that they could first support strengthening, then depression, was really surprising.”

If NMDA receptor activation eventually leads to synaptic depression, then what might happen if those NMDA receptors are blocked? Clem and colleagues found that the NMDAR blocker APV (D,L-2-amino-5-phosphonovaleric acid) prevented synaptic depression. In the presence of APV, synaptic activity continued to increase in response to SWEs. However, this synaptic strengthening was abolished if the researchers also added the broad spectrum mGluR antagonist MCPG ([RS]-a-methyl-4-carboxyphenylglycine). The findings suggest that there is initially an NMDA-driven increase in synaptic activity, followed by an NMDA-driven weakening that is overcome by metabotropic glutamate receptors. “Thus, after the onset of experience-dependent plasticity in the spared barrel column, mGluRs can oppose NMDAR-mediated synaptic depression in vitro,” write the authors.

Barth believes that these findings are physiologically relevant because blocking mGluRs eliminates learning. The researchers used an associative learning task, where whisker stimulation is the conditioned stimulus, to probe the effects of NMDA-related depression and mGluR-driven synaptic strengthening. They found that the CPP antagonist enhanced associative learning while the mGluR1 antagonist AIDA reduced it.

It is not immediately clear if this new phenomenon has any bearing on the pathology of schizophrenia; however, glutamatergic dysfunction is a well-established facet of the disease (see related SRF hypothesis), and the recent positive findings from the Phase 2 trial of the mGlu2/3 agonist LY404039 shows that mGluR targeting can be an effective antipsychotic strategy (see SRF related news story). There is also recent evidence for disrupted LTP in patients (see Frantseva et al., 2007), and, in keeping with this finding, the NMDA receptor blocker MK801, which causes psychosis in humans, impairs LTP in rats (see Manahan-Vaughan et al., 2008). More specifically, there is evidence that metabotropic glutamate receptors may play a role in pathology since loss of mGluRs in experimental animal models causes symptoms akin to those found in schizophrenia patients, such as disrupted prepulse inhibition (see Brody et al., 2003).

Though there are eight different varieties of metabotropic glutamate receptors (acting pre- and postsynaptically), which complicates interpretation of some findings, they have been considered drug targets for a variety of neurological disorders, including schizophrenia, Alzheimer’s, Parkinson's, and Huntington's diseases (for a review, see Ritzen et al., 2005). In fact, the recent positive mGlu2/3 trial could herald a new era of treatment for schizophrenia, since all antipsychotic drugs used to date target the dopaminergic system. In addition, an mGluR1 modulator, AZD9272, is currently undergoing trials for schizophrenia (see SRF Drugs in Clinical Trials) and just last week Pfizer Inc. announced an agreement with the Japanese company Taisho Pharmaceutical to develop their mGluR1 agonist TS-032 for schizophrenia as well (see Pfizer press release). Similarly, Merck & Co., Inc. will develop an mGluR5 drug from the Swiss Addex Pharmaceuticals (see Addex press release).—Tom Fagan.

Clem RL, Celikel T, Barth AL. Ongoing in vivo experience triggers synaptic metaplasticity in the neocortex. Science 2007 Jan 4;319:101-104. Abstract

Brecht M, Schmitz D. Neuroscience. Rules of plasticity. Science. 2008 Jan 4;319(5859):39-40. PMID: Abstract

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