Colorado State University Research Finds First Known Synaptic Activity Control Mechanism

A Colorado State University study published today in Nature Neuroscience outlines the discovery of a new mechanism that regulates how the brain manages a constant balance of activity, preventing neural circuits from becoming overloaded or under-stimulated. The discovery may help scientists develop drugs to counter epilepsy, Alzheimer’s, stroke or other brain-activity related disorders.

Synaptic homeostasis— the active maintenance of neuronal signaling within a stable range of activity – is essential for normal brain function because the brain is continuously confronted with changes in activity during learning and development or as a result of pathological conditions. While researchers have identified multiple cellular mechanisms that reduce or boost brain activity when activity is heightened or lowered, scientists until now have not found mechanisms that they knew must be finely regulating these homeostatic responses to prevent over-compensation, which would also be detrimental.

“Maintaining activity within an acceptable range works somewhat like a thermostat,” said Susan Tsunoda, a biomedical sciences professor at CSU. “That is, when activity is too high, synapses react by downgrading activity, and when activity is too low, synapses respond by boosting activity.

“We found that homeostatic mechanisms trigger a secondary mechanism that dampens or regulates the homeostatic response,” said Tsunoda, whose research was conducted on fruit flies, commonly used in genetic studies. “Our study discovered how this regulatory mechanism is activated and brain activity is stabilized. The results of this study will help us to better understand how neural circuit activity in the brain is stabilized in response to changes in stimulation.”

Tsunoda and her colleagues’ finding of this regulatory mechanism, mediated by a specific type of potassium channel, is believed to be the first identified mechanism triggered by homeostasis to stabilize signaling.

Neural activity in the brain is continuously regulated to maintain a proper balance between too much and too little activity to prevent the brain from overworking or not functioning enough. This is a challenge for the brain since neural circuits are constantly confronted with changes in activity from normal physiological function during learning and development and from pathological conditions such as seizures, Alzheimer’s disease and even nicotine exposure.

Potassium channels are important for electrical signaling within a single brain cell as well as for regulating and integrating incoming signals coming from other brain cells. There are many different potassium channels, but Tsunoda’s lab is focused on a particular channel, called the Shal K+ channel. These channels are very similar in all species.

“Of course, with every question we answer, many more questions arise,” Tsunoda said. “The take-away for us is that we have this regulatory system, but what does it really do? It is an important phenomenon – that brain activity should be tightly regulated and controlled. If the brain is not regulated properly, what will happen? Could something like homeostasis be involved in neurological diseases like Alzheimer’s or other pathological conditions such as drug addiction? We are just beginning to explore these possibilities.”

Tsunoda is now working to better tease out the signaling pathways from inactivity to a precisely tuned homeostatic response.

“At the end, we are looking at synaptic potentials,” Tsunoda said. “One neuron talking to another neuron, and what happens if we dampen this communication. How will things change? What happens without homeostasis regulation? Right now, we don’t know.”

Tsunoda’s research is supported by the National Institute of General Medical Sciences, part of the National Institutes of Health. She works in the university’s College of Veterinary Medicine and Biomedical Sciences.