All mental processes, including thinking, learning and memory, depend on the electrical properties of individual nerve cells in the brain and on the connections between them. In turn, the electrical responses of each nerve cell, or neuron, reflect the unique set of pores — called ion channels — that perforate its surface and allow the passage of charged particles, or ions.
So researchers at Washington University School of Medicine in St. Louis were a little surprised when they saw no harmful effects in mice after eliminating an important type of potassium ion channel from neurons in the brain.
In physiological studies, they demonstrated that the brain made up for the missing ion channels by increasing production of other ion channels. They believe this is an important way for neurons to function consistently in the face of cellular changes that happen during normal brain development, during the processes of learning and memory formation and perhaps after brain injury. Understanding the underlying molecular mechanisms could lead to targeted treatments for many nervous system disorders, such as epilepsies, based on regulating the function of particular types of ion channels.
“We eliminated a gene that encodes a type of potassium ion channel in mice, and we found that neurons in the brain’s cortex effectively compensated for this loss,” says first author Jeanne M. Nerbonne, Ph.D., the Alumni Endowed Professor of Molecular Biology in the Department of Developmental Biology.
Senior author Andreas H. Burkhalter, Ph.D., professor of anatomy and neurobiology says, “Essentially, the neurons fought back by generating new channels, and the end result is that neurons and neuronal circuits maintain stability.”
Potassium ion channels affect how neurons receive, process and transmit neuronal impulses. Several kinds of potassium ion channels exist, with each class responding in a unique way to changing conditions in the active brain.
The research team examined neurons isolated from the brain cortex of mice missing one potassium ion channel gene (KCND2). In humans, the cortex, the outermost layer of the brain, is responsible for memory, attention, perceptual awareness, thought, language and consciousness.
Nerbonne, Burkhalter and colleagues found that the neurons without the KCND2-encoded potassium ion channels made much more of two other kinds of potassium ion channels. Using instruments that allow measurement of the electrical properties of individual neurons, they found that a potassium ion current previously believed to control repetitive firing of neurons was eliminated. The currents associated with the two up-regulated potassium ion channels rose.
Still, the overall firing properties of these neurons were remarkably similar to control nerve cells that had the normal compliment of KCND2-encoded potassium ion channels, suggesting that electrical remodeling occurs to maintain neuronal function.
“We are particularly interested in the regulation of neuronal potassium ion channel expression and function because these channels appear to play critical roles in the fine tuning of neuronal membrane excitability,” Nerbonne says.
The findings of this study, reported in the March 15, 2008, issue of the Journal of Physiology, indicate that nerve cells can sense alterations in their ion channels and find ways to overcome them. Understanding more fully how this happens will offer better insight into brain function and neural disorders. Already researchers know that a mutation in the KCDN2 locus in humans is linked to temporal lobe epilepsy, a disorder in which seizures arise from the parts of the brain responsible for speech, memory and learning.
With Colin G. Nichols, Ph.D., the Carl Cori Professor of Cell Biology and Physiology, Nerbonne is co-director of the Center for the Investigation of Membrane Excitability Disorders (CIMED), one of the Interdisciplinary Research Centers of BioMed 21, the University’s initiative dedicated to rapidly translating laboratory discoveries into new approaches for patient diagnosis and treatment.
Ion channels are an important aspect of nerve communication, muscle contraction, hormone secretion, cell division and immune function, to name just a few. CIMED focuses on gaining a better understanding of ion channel functioning and regulation to aid in the development of new treatments for diseases as wide ranging as cystic fibrosis, epilepsy, migraine, abnormal heart rhythms and type 2 diabetes.