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CAI Neurons Implicated in Rare Form of Transient Global Amnesia

ARTICLE IN BRIEF

Investigators reported that high-resolution MRI scans performed 24 to 72 hours after the acute phase of transient global amnesia revealed highly focal lesions that were confined to the cornu ammonis 1 field of the hippocampus.

An experiment involving humans with a rare form of amnesia has verified that cornu ammonis 1 (CA1) neurons in the hippocampus are essential for encoding spatial memories.

The study, published in the June 11 issue of Science, involved 14 people who developed acute transient global amnesia (TGA), a dysfunction of the hippocampus that causes complete loss of the ability to record declarative memories for up to 24 hours. High-resolution MRI scans performed 24 to 72 hours after the acute phase of the illness revealed highly focal lesions that were confined to the CA1 field of the hippocampus.

After their amnesia resolved, the 14 TGA patients performed just as well as 14 controls in tests of verbal, cognitive, attentional, and general intellectual abilities. However, differences emerged when they were trained to operate a computer simulation based on the Morris water maze, used to test the ability of laboratory rodents to find and remember the location of a platform submerged in a pool of opaque water.

In the virtual water maze, participants using a computer joystick were asked to explore an island displayed on the monitor until they located a hidden treasure box near the lighthouse. In the initial trial the box was marked by a balloon. Landmarks including the lighthouse, a windmill, a yacht, and a sea buoy helped the participants remember the location of the box.

DR. THORSTEN BARTSCH

said these results, combined with the absence of lesions in other brain regions of TGA patients, demonstrate that the CA1 neurons are crucial for spatial navigation.

In the recall phase of the trial, participants were expected to find the box using landmarks. The controls, using landmarks, approached the box directly, while the TGA patients wandered, apparently searching for the box randomly. “[T]hey exhibited no systematic search behavior,” the authors stated. TGA patients with larger CA1 lesions and longer-lasting symptoms tended to do worse.

These results, combined with the absence of lesions in other brain regions of TGA patients, demonstrate that the CA1 neurons are crucial for spatial navigation, according to the lead author of the Science paper, Thorsten Bartsch, MD, of the Department of Neurology of University Hospital Schleswig-Holstein in Kiel, Germany.

“Spatial navigation depends on a widespread network involving temporal, parietal, and perhaps frontal cortical networks,” he said. “The CA1 neurons are the major relay for output from the hippocampus, and if you perturb these neurons, that would be enough to disrupt the entire network and knock out spatial navigation function.”

THEORIES ABOUT TGA ETIOLOGY

TGA, which tends to come on suddenly following physical exertion, sexual intercourse, or extreme emotional stress, produces profound loss of memory for recent events, and an inability to form new memories. First described in 1956, the cause has remained mysterious. In a 2008 paper in Neurology, Dr. Bartsch and colleagues reported finding a lactate peak in the CA1 lesions of the hippocampus of four of seven patients with TGA who underwent MR spectroscopy. This suggests that acute metabolic stress produced dysfunction in those neurons, the authors wrote.

Although TGA bears no relationship to Alzheimer disease, both disorders involve disruption of the CA1 neurons, and produce similar symptoms. Dr. Bartsch suspects this may be due, at least in part, to the excitotoxic effect of glutamate transmission when it is released following an insult to the brain.

“The CA1 region is metabolically very vulnerable,” he said. “This area has abundant glutamatergic projections, and if excessively liberated, glutamate has a cytotoxic effect. There's a fine line between maintaining the critical relay function of the CA1 region, which is glutamate dependent, and disrupting it with excessive stimulation by glutamate.”

ROLE IN SPATIAL MEMORY

Experiments conducted over many years, most notably by John O'Keefe, PhD, and colleagues at University College London, have shown that the hippocampal CA1 neurons of animals are critical to the navigation and the consolidation of spatial memories. Lesions to that area produce impairments in spatial memory and disrupt the ability to build new mental maps of an area.

DR. ARNE EKSTROM:

“In particular, I think it will lead to a greater focus on how this subregion might contribute to diseases like Alzheimers, which produce problems in spatial memory. Right now we dont have well-developed techniques for imaging activity in subregions of the hippocampus because these regions are small — on the order of millimeters in some places — and generally difficult to image with current methods.”

A 2003 Nature paper reported a similar correlation in humans. Using single cell recordings from a total of 317 electrodes that had been implanted by physicians in seven patients with intractable epilepsy in an effort to locate the focus of their seizures, the authors found that activity in the hippocampus occurred when the patients viewed specific locations in a virtual town they were exploring on a computer screen. In addition, neurons in the parahippocampal cortex of the subjects increased their firing rate when the subjects viewed familiar landmarks. This demonstrated that humans not only have neurons in the hippocampus that enable them to produce a mental map of a place, as do rats, but they also have neurons in other brain regions that respond to familiar landmarks.

EXPERTS COMMENT

“Together, these make up important components of how we know where we are, based both on where we are standing and on what we see,” said Arne Ekstrom, PhD, the lead author of the 2003 Nature paper.

Dr. Ekstrom considers the work of Dr. Bartsch and his colleagues to be “a significant contribution” to understanding what the hippocampus does. “I think it implicates place coding not just in the hippocampus, which is what my paper showed, but specifically in a subregion of the hippocampus — the CA1,” said Dr. Ekstrom, assistant professor at the Center for Neuroscience of the University of California-Davis. “That's a significant step forward.”

Dr. Ekstrom believes the Science paper will have an impact on research into Alzheimer disease and memory in general. “I think it will lead researchers to focus more on the contribution of the CA1 area of hippocampus to memory,” he said. “In particular, I think it will lead to a greater focus on how this subregion might contribute to diseases like Alzheimer's, which produce problems in spatial memory. Right now we don't have well-developed techniques for imaging activity in subregions of the hippocampus because these regions are small — on the order of millimeters in some places — and generally difficult to image with current methods.”

Dr. Bartsch acknowledged that the findings obtained from TGA patients would have been impossible without the widespread availability of high-resolution MRI equipment. “Normal MRI imaging has reached such a high level of resolution that we now can reliably detect these lesions in these patients,” he said.

Eric Kandel, MD, who won the 2000 Nobel Prize in Physiology or Medicine for his lifelong research on the physiological basis of memory, expressed admiration for the Science paper. “To use global amnesia, which is a temporary impairment of explicit memory – that's a wonderful idea,” said Dr. Kandel, University Professor and Fred Kavli Professor and Director of the Kavli Institute for Brain Science at the Columbia University College of Physicians and Surgeons.

“It is not surprising that CA1 is critical for spatial memory. All the rodent work shows that. And we've known from imaging studies done in England that taxi drivers in London, who have to know their way around London, the longer they've driven the larger their hippocampus,” he said. “And when they think about how to go from one place to another, their hippocampus lights up. They clearly recruit the hippocampus for spatial memory. This paper is a confirmatory story done in an extremely interesting clinical context that shows that what we suspected from studies on rodents applies to people.”

DR. ERIC KANDEL:

“It is not surprising that CA1 is critical for spatial memory. All the rodent work shows that. …This paper is a confirmatory story done in an extremely interesting clinical context that shows that what we suspected from studies on rodents applies to people.”

REFERENCES:

Bartsch T, Schönfeld R, Koch JM, et al. Focal lesions of human hippocampal CA1 neurons in transient global amnesia impair place memory. Science 2010 328: 1412-1415.
    Bartsch T, Alfke K, Deuschl G, et al. Focal MR spectroscopy of hippocampal CA-1 lesions in transient global amnesia. Neurology 2008;70:1030-1035.
      Cejas C, Cisneros LF, Ameriso SF, et al. Internal jugular vein valve incompetence is highly prevalent in transient global amnesia. Stroke 2010; 41:67-71.
        Ekstrom AD, Kahana MJ, Fried I, et al. Cellular networks underlying human spatial navigation. Nature 2003;425(6954):184-188.