Do Neurons Get Overexcited Too? A Perspective on Learning and Epilepsy

Anita Bandrowski
Department of Neurology
Stanford University
March 2002

Communication between neurons is crucial for detecting the presence of your mother in the room, changing your heart rate, putting away the gift that you did not want her to see, and learning that it is important not to forget a birthday. Too much neuronal communication and subsequent over-excitement, on the other hand, is related to diseases such as epilepsy. In epilepsy, typically one group of cells begins to behave abnormally and often spreads this abnormal activity to other cells, which for the person suffering from the disease means lapses in consciousness or overt muscle convulsions. My research focuses on answering questions such as "does this small increase in communication generate a lasting memory?" and "is this slightly larger increase in neuronal communication producing epileptic seizures?"

Neuronal communication is accomplished by passing information from one cell to another, which in turn passes the information to yet another cell. This type of communication is similar to a game called "telephone" in which children line up and whisper information from one person to the next. In the case of neurons, however, each neuron often has thousands of other neurons that it can communicate with. In the game, each child attempts to pass accurate information, but the information can be misinterpreted by the next child. Similarly, the proteins involved in the listening process can misinterpret the information between cells. The misinterpretation of information can lead to a breakdown of the system where children begin to laugh, signaling the end of the game. When neurons stop talking, however, neuronal processing of other types can shut down, leading to much more serious consequences. Epilepsy researchers have paid a great deal of attention to neuronal communication because neurons within the seizure focus, the point at which the seizure is generated, can communicate in a way that normal signals are misinterpreted, and this misinterpretation can lead to hyperactivity and the generation of the seizure. Additionally, the abnormal signals can spread from one group of somewhat unhealthy cells and become generalized, that is they involve other healthy brain regions. Therefore, studying communication between neurons not only can answer questions about seizure generation, but also about the spread of seizure.

There are several classes of "listening" or receptor proteins positioned to "hear" the information coming from their neighbor cells. These receptor proteins can be divided into two major classes. The first is ionotropic, which is responsible for detecting the presence of a signal, and the other is metabotropic, which is responsible for modifying the information. The two-tiered information processing system allows very important information to be preferentially treated so that many systems become involved in its processing. For example, the sight of your mother while you are hiding her birthday present would be a piece of information that would elicit multiple behavioral effects such as a limbic response, vasodialation in the face (flushing) or an increase in heart rate.

To measure the information that is "heard" by a neuron, it is possible to visualize, using a microscope, a living neuron and inserting a very small electrode into it. The electrode can "listen" in on the ongoing electrical activity, and this activity can be recorded using a high-powered amplifier and a computer. Various pharmacological tools, i.e. drugs, can bind to receptor molecules and modify their activity, which has secondary effects on the ongoing neuronal activity. Using these types of tools, I have found that metabotropic glutamate receptors, a metabotropic receptor that "hears" signals being passed via the glutamate molecule, are involved in learning. Activation of these receptors can modify the response to the original signal, enough to cause a long lasting "memory" of that signal. This memory manifests itself as a response that is larger in size than the original response to the same signal. By studying the rat brain, I am presently interested in determining whether the increase in response size, which is elicited by metabotropic glutamate receptors, can ever get large enough to trigger an epileptic episode. If so, I can then ask whether these receptors participate in ongoing seizures in epileptic mice and eventually in epileptic patients. If it could be determined that the metabotropic glutamate receptors are involved in epilepsy, then these receptors become a new target for intelligent drug design. Unfortunately, there are many epileptics who do not respond well to conventional medication, and therefore development of new classes of drugs adds choices for doctors and patients.