We study the basic biology of neurologic disorders such as epilepsy. Our work is at the interface of molecular biology and electrophysiology of brain neurons. One of our main

projects is to study epileptogenesis, the process by which a normal brain is converted to one with epilepsy. Right now there's no therapeutic strategy that can prevent epilepsy in people at risk, and that's one of our goals.

This line of practical research has benefited from our basic work on glutamate receptors. My own work has progressed in two directions that have periodically intersected. One is the pharmacology of glutamate receptors, especially modulatory sites on them, and the second is studying epilepsy.

Glutamate is a simple amino acid that acts on neurotransmitter receptors to mediate communication between neurons of the brain. Glutamate receptors are the most prevalent excitatory neurotransmitter receptor in the brain, and they mediate almost all excitatory communications among neurons. The glutamate receptors have binding sites for glutamate, but they’re also ion channels, so when glutamate binds, the channel opens, and ions flow through the channel to set up electrical communication between neurons.

Epileptic seizures are a problem of overactivation of brain neurons that are driven mainly by glutamate synapses. So developing new strategies for seizure control can benefit by understanding glutamate receptor protein physiology.

  How did you become interested in this area?

I first became interested in epilepsy as a postdoc in the lab of Per Andersen in Oslo, Norway, in 1977-78.  There I was introduced to the hippocampus, which is a really beautiful structure in the brain that plays host to a number of central questions and issues in neuroscience, including memory and epilepsy. The Andersen lab was studying the hippocampus circuitry that mediates epileptic seizures and learning. I became fascinated with the problem.

Then after a couple of years I realized I couldn't get very far just studying the circuitry, but that I had to understand the molecular properties of the receptors that mediate transmission, which led me to glutamate and, eventually, to the molecular biology of their receptors.

So my own research career has evolved in jumps. I started out in brain-slice electrophysiology. Then we modified a new frog oocyte preparation to study glutamate receptors and more recently incorporated molecular biology and genomics into this work.

  What do you think is driving the high citation rate of your lab's papers?

I suspect that it reflects the central role that glutamate receptors play in a number of brain processes. I mentioned epilepsy, but these receptors also play a role in Parkinson’s disease and brain damage following stroke, and are important for circuits key to memory and learning. These findings, from many labs, have attracted a large number of neurologists, physiologists, pharmacologists, and anatomists who are interested in the properties of glutamate receptors. It's a wide field right now.

  What are some of the greatest challenges in performing your work?

There are some generic challenges in time management and holding research groups together long enough to really accomplish something. We've had a stream of technical hurdles that we've always seemed to overcome, but maybe one of the most persistent challenges in the last 10 years has been to find ways to forge real links between the molecular biologists and physiologists in my lab, so they have something to talk about that is meaningful to both sides.

It's a challenge because the vocabulary and orientation and outlook are generally different between the two groups. Molecular biology is a very reductive discipline, whereas the physiologists are much more systems-oriented and interested in the function of a brain region. I think we've managed recently to build a bridge between these two disciplines by identifying a genomic-level mechanism by which gene expression is changed in epilepsy. And to do that we've had to have real coordination and cooperation among everyone in the lab.

  What would you like to convey to the general public about your work?

It's important to know that pharmacology as a field exists to lay the groundwork for the discovery and development of the next generation of drugs. That's what we're pointed towards. It’s also important to recognize that there's a good deal of basic scientific research behind any drug that's on the market.

  What lessons would you draw from your work to pass on to the next generation of researchers?

What I do recommend is to hone your sense of when to quit a project. In the long run, folding your hand early rather than spending time unfruitfully is good advice. Second, and not necessarily self-evident to students, expect to change research directions several times in your career and look for opportunities to take advantage of new discoveries or new technologies in other fields, because often it's the interface between two fields that yields the most interesting direction.

  What are the implications of your work for the future of your field or neighboring fields?

One thing we've managed to do is help understand how glutamate receptors are modulated and activated. This information is critical for developing drugs against these receptors. One of our goals is to identify drugs that modify rather than block or activate receptor function. Experience with other receptors shows that modulators are better tolerated by the body.

  How rapidly has the state of knowledge in your field evolved in the past decade, and what are the key discoveries associated with that?

Our field has evolved in spurts and now we're miles ahead of where we were in 1990. Twelve years ago we thought there were almost certainly glutamate receptors because of the different pharmacological responses of glutamate-mediated activity in brain tissue. But no one had really isolated a receptor. In 1989 the first glutamate receptor subunit was cloned, and that led, within about 5 months, to the cloning of the next five, and then in the subsequent year and a half, to the cloning of all 16 receptor subunits.

Cloning these receptors has provided a real boost to the field because it triggered a blitz of molecular genetics and mutation analyses of receptor structure and function in the 1990s. Then in 1999, the binding site on one of the receptors was crystallized, so we now have its structure. That hasn't borne a good deal of fruit yet, but I expect that knowing the crystal structure will provide the same kind of pump to the field that the cloning did.

  What is your prediction for the state of knowledge about your field 10 years from now?

I expect that the fields of cell biology and systems physiology in the brain will merge. There are so many molecular events now demonstrated to influence synaptic transmission, and so much effort being put on finding the links between the properties of individual synapses and circuits that I think these fields will come together.

I also suspect that genomics technologies will reveal a strategy to prevent epilepsy in those people at risk. Because it seems that neuron loss is involved in the early stages of epileptogenesis, my guess is that such a strategy could be useful for other conditions like stroke, Alzheimer’s, and Parkinson’s—all diseases that involve neuron death.