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Surprising Discoveries Contribute to Memory Research

A Northwestern research team reports discovering a new cellular mechanism that could be critical to the formation of memories.

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January 1, 2009 | by Megan Fellman
EVANSTON, Ill. --- Like countless neuroscientists around the world, Northwestern University Professor Nelson Spruston knew H. M. well -- his personal story and the sound of his voice. But it wasn't until H. M. died last month that Spruston learned H. M.'s full name -- Henry Gustav Molaison.

In 1953, Molaison, aged 27, had brain surgery to control his severe epilepsy. Both medial temporal lobes were removed, the first and only surgery of its kind. His seizures improved, but he became frozen in time, unable to form new and lasting memories. When Molaison died, his body was 82, but his mind and personality were in many ways still 27.

Molaison's experience has pointed Spruston and other scientists interested in understanding learning and memory to the temporal lobe, particularly the hippocampus. In a new study to be published in the Jan. 29 issue of the journal Neuron, Spruston and his research team report discovering a new cellular mechanism that could be critical to the formation of memories in the hippocampus.

Something in the brain must change in response to experience in order for individuals to learn. Spruston and his colleagues studied the electrical output of neurons and discovered that two different types of neuronal metabotropic receptors together produce biochemical changes that change the way a neuron fires, increasing the neuron's electrical output and strengthening the signals it sends to other brain regions, including those involved in reward and decision making.

Two things were particularly surprising to the researchers. First, the change, or plasticity, requires both receptors to be biochemically stimulated, not just one or the other. Second, the change in output occurs independent of any electrical stimulation or synaptic change.

"We've identified an important molecular target inside the hippocampus -- the metabotropic receptors -- that will help us better understand learning and memory," said Spruston, professor of neurobiology and physiology in the Weinberg College of Arts and Sciences at Northwestern. He led the research team.

The two types of metabotropic receptors appear to form a "coincidence detection" system, detecting two things happening at once and forming associations between the separate neural events. Coincidence detection is important when a person associates a smell with a specific memory or assigns importance to an event.

"As we've learned from Molaison, the biological machinery responsible for learning and memories is localized in the brain. Changes in the hippocampus are essential for our very personalities -- who we are and the place we have in the world. I hope that our study increases attention on the role of metabotropic receptors in the neural changes that produce memories," added Spruston.

Spruston's team studied the subiculum, an important area of the hippocampus that shows deterioration in Alzheimer's disease and also is an output pathway to other brain regions related to schizophrenia and addiction.

Synaptic plasticity, in which the connection, or synapse, strengthens between two neurons as a result of learning, has received the most attention and study. Spruston focused on a less-studied process, that of non-synaptic plasticity. The output of the hippocampus (from the subiculum) also has not received much attention.

"I think Nelson is on to something very fundamental that has been essentially untouched in the mammalian brain," said Nobel Laureate Eric R. Kandel, M.D., University Professor and Kavili Professor of Brain Science at Columbia University. Kandel began studying the hippocampus, including metabotropic receptors, and its role in memory in the 1950s.

The work was supported by the National Institutes of Health.

In addition to Spruston, other authors of the Neuron paper, titled "Plasticity of Burst Firing Induced by Synergistic Activation of Metabotropic Glutamate and Acetylcholine Receptors," are Shannon J. Moore (lead author), from Northwestern, and Donald C. Cooper, a former postdoctoral fellow in Spruston's lab, now at the University of Texas Southwestern Medical Center.

National Public Radio story on H.M. (Weekend Edition Saturday, February 24, 2007)