Astrocytes — not neurons — found to control the brain’s gamma waves and some forms of memory

Cells thought to play only supporting roles demonstrate surprising effects on object-recognition memory and cognitive behavior
July 30, 2014

Terrence Sejnowski, Professor and Laboratory Head of the Computational Neurobiology Laboratory (credit: Salk Institute for Biological Studies)

In a study published July 28 in the Proceedings of the National Academy of Sciences, Salk Institute for Biological Sciences researchers have found that brain cells called astrocytes — not neurons — can control the brain’s gamma waves.

They also found that astrocytes — a type of glial cell traditionally thought to provide more of a support role in the brain — and the gamma oscillations they help shape are critical for some forms of memory, such as object recognition.

(When you’re expecting something or when something captures your interest, unique high-frequency electrical rhythms called gamma waves sweep through your brain. Gamma waves have been associated with higher-level brain function, and disturbances in the patterns have been tied to schizophrenia, Alzheimer’s disease, autism, epilepsy and other disorders.)

Evidence linking gamma waves with attention and memory, influenced by astrocytes

“This is what could be called a smoking gun,” says co-author Terrence Sejnowski, head of the Computational Neurobiology Laboratory at the Salk Institute for Biological Sciences, a Howard Hughes Medical Institute investigator. “There are hundreds of papers linking gamma oscillations with attention and memory, but they are all correlational. This is the first time we have been able to do a causal experiment, where we selectively block gamma oscillations and show that it has a highly specific impact on how the brain interacts with the world.”

A collaboration among the labs of Salk professors Sejnowski, Inder Verma, and Stephen Heinemann found that activity in the form of calcium signaling in astrocytes immediately preceded gamma oscillations in the brains of mice. This suggested that astrocytes, which use many of the same chemical signals as neurons, could be influencing these oscillations.

In the hippocampus (the part of the brain that controls memory), normal astrocytes (red) and neurons (blue) are imaged. When tetanus toxin is added, only the astrocytes are affected, as shown by the yellow area in the image (right) with astrocytes and neurons superimposed. This exclusive reaction to the toxin allowed scientists to show that reduced activity in astrocytes interfered with new memory formation in behavioral tests. (Credit: Salk Institute for Biological Studies)

To test their hypothesis, the group used a virus carrying tetanus toxin to disable the release of chemicals released selectively from astrocytes, effectively eliminating the cells’ ability to communicate with neighboring cells. Neurons were unaffected by the toxin.

After adding a chemical to trigger gamma waves in the animals’ brains, the researchers found that brain tissue with disabled astrocytes produced shorter gamma waves than in tissue containing healthy cells. And after adding three genes that would allow the researchers to selectively turn on and off the tetanus toxin in astrocytes at will, they found that gamma waves were dampened in mice whose astrocytes were blocked from signaling. Turning off the toxin reversed this effect.

Unexpected effects on object recognition and cognitive behavior

The mice with the modified astrocytes seemed perfectly healthy. But after several cognitive tests, the researchers found that they failed in one major area: novel object recognition. A healthy mouse spent more time with a new item placed in its environment than it did with familiar items, as expected.

In contrast, the group’s new mutant mouse treated all objects the same. “That turned out to be a spectacular result in the sense that novel object recognition memory was not just impaired, it was gone — as if we were deleting this one form of memory, leaving others intact,” Sejnowski says.

The results were surprising, in part because astrocytes operate on a seconds-or-longer timescale, whereas neurons signal far faster, on the millisecond scale. Because of that slower speed, no one suspected astrocytes were involved in the high-speed brain activity needed to make quick decisions.

“What I thought quite unique was the idea that astrocytes, traditionally considered only guardians and supporters of neurons and other cells, are also involved in the processing of information and in other cognitive behavior,” says Verma, a professor in the Laboratory of Genetics and American Cancer Society Professor.

It’s not that astrocytes are quick — they’re still slower than neurons. But the new evidence suggests that astrocytes are actively supplying the right environment for gamma waves to occur, which in turn makes the brain more likely to learn and change the strength of its neuronal connections.

Sejnowski says that the behavioral result is just the tip of the iceberg. “The recognition system is hugely important,” he says, adding that it includes recognizing other people, places, facts and things that happened in the past. With this new discovery, scientists can begin to better understand the role of gamma waves in recognition memory, he adds.

Collaborators included researchers at Sogang University in South Korea, University of Lisbon in Portugal, University of Sassari Medical School in Italy, and Scripps Research Institute in La Jolla, California.

The work was supported by a Salk Innovation Grant, Kavli Innovative Research Awards, a Calouste Gulbenkian Foundation Fellowship, a Life Sciences Research Foundation Pfizer Fellowship, the Brain and Behavior Research Foundation, the Bundy Foundation, Jose Carreras International Leukemia Foundation, the Pew Charitable Trusts, National Science Foundation, Howard Hughes Medical Institute, the Office of Naval Research, and the National Institutes of Health.

Abstract from PNAS paper

Glial cells are an integral part of functional communication in the brain. Here we show that astrocytes contribute to the fast dynamics of neural circuits that underlie normal cognitive behaviors. In particular, we found that the selective expression of tetanus neurotoxin (TeNT) in astrocytes significantly reduced the duration of carbachol-induced gamma oscillations in hippocampal slices. These data prompted us to develop a novel transgenic mouse model, specifically with inducible tetanus toxin expression in astrocytes. In this in vivo model, we found evidence of a marked decrease in electroencephalographic (EEG) power in the gamma frequency range in awake-behaving mice, whereas neuronal synaptic activity remained intact. The reduction in cortical gamma oscillations was accompanied by impaired behavioral performance in the novel object recognition test, whereas other forms of memory, including working memory and fear conditioning, remainedunchanged. These results  support a key role for gamma oscillations in recognition memory. Both EEG alterations and behavioral deficits in novel object recognition were reversed by suppression of tetanus toxin expression. These data reveal an unexpected role for astrocytes as essential contributors to information processing and cognitive behavior.