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L'X fragile sera vaincu | Fragile X will be conquered

The Glutamate System: A Breakdown of the Neurobiology, and Current Therapeutic Research

Psychiatry Weekly, Gerard Sanacora, MD, PhD – Professor of Psychiatry and Director of the Yale Depression Research Program School of Medicine, Yale University

This interview was conducted on June 24, 2010 by Norman Sussman, MD


Glutamate is the primary neurotransmitter in the human brain. It was, however, one of the later neurotransmitters discovered, because it is literally one step off the Krebs cycle, and a critical component of general energy metabolism.

“Put glutamate in perspective this way:” says Dr. Gerard Sanacora. “If you add the number of neurons that are using serotonin, norepinephrine, dopamine, and some acetylcholine, they usually account for ~5% of the neurons in the brain, whereas glutamate and GABA make up ~50% and ~45%, respectively.”

The Mechanics of the Glutaminergic Spectrum

“There are two major classes of glutamate receptors: ionotropic and metabotropic.” says Dr. Sanacora. “The ionotropic receptors are very rapidly acting ion channels that allow either calcium or sodium to pass when glutamate binds. The metabotropic receptors act through G protein mediated systems, so they are thought to be slower acting and to modulate the effects of glutamate. Then within the ionotropics there are two major types of receptors: the NMDA receptor and the AMPA receptor.”

The NMDA receptor antagonist, ketamine, is an anesthetic agent that has recently become known for its antidepressive effects. Ketamine blocks the NMDA receptor, which limits the flow of calcium into the cell. It is unclear what mechanism might account for ketamine’s antidepressant effects, because, as Dr. Sanacora explains, ketamine paradoxically causes a release of glutamate.

“Blocking the NMDA receptor postsynaptically apparently causes a bolus release of glutamate from the presynaptic cell,” he says. “That leads to increased activation of some other glutamate receptors, including the AMPA receptor. The antidepressant effects of ketamine were blocked in two independent animal studies by giving an AMPA blocker. This suggests that the blockade of NMDA may be of secondary importance to the release of glutamate and stimulation of the AMPA receptor. Alternatively, it could be the ratio of NMDA to AMPA activation that is critical in producing the response.”

Therapeutic Potentials

Agents that block glutamate are well known to have an anesthetic effect. Increasing glutamate excitability, on the other hand, usually causes either excitotoxicity or seizure. Greater efforts have been underway in recent years to modulate this system in such a way to prevent the onset of seizure and excitotoxicity.

Several agents acting primarily on the glutamate system already hold a well-established benefit for psychiatric disorders. The efficacy of lamotrigine (a drug that modulates glutamate release) for bipolar disorder is the best documented. Memantine, an NMDA antagonist similar in some ways to ketamine, is indicated for treatment of Alzheimer’s disease.

Open-label studies of riluzole, which appears to modulate glutamate release and facilitate glutamate clearance, and is indicated for the treatment of Lou Gehrig’s disease, have reported favorable effects in patients with treatment-resistant bipolar depression, generalized anxiety disorder, and treatment-resistant unipolar depression.

“Research by Mark Bear and others suggests that metabotropic glutamate 5 receptor (mGluR 5) has a big determinant over local protein synthesis at the synapse,” says Dr. Sanacora. “Stimulation of the mGluR 5 tends to rev up local protein synthesis, opposing the effects of the fragile X protein, the role of which seems to be to decrease local protein synthesis. Fragile X protein knockout mice exhibit many of the features of fragile X. But if you give an mGluR 5 antagonist, you can reverse all of those things, except for the macroorchidism. This was described as a balancing act between maintaining local protein synthesis and spine density. Fragile X is associated with long, flimsy dendritic spines. Blocking mGluR 5 in the Fragile X protein knockout mice normalizes spine shape and density. So the spines look more normal, and the behaviors look more normal. This is quite exciting from a neuroscience perspective. This mGluR 5 antagonist may, hopefully, be translated not only to fragile X but maybe to autism, as well, since there is some evidence that autism might be involved in the same spine-density abnormalities.”


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