It is known that children who experience seizures early in life are at risk for long-term cognitive damage, but exactly how seizures affect the developing brain has remained a mystery until now. A recent paper titled “Early life seizures cause long-standing impairment of the hippocampal map,” written by Dartmouth alumnus Havisha Karnam and Dartmouth Medical School professor Gregory Holmes, suggests that seizures cause impairment in spatial learning and damage to the hippocampus place cells, which provide individuals with a spatial map.
Since developing rats experience the same cognitive ability deficit as children after a seizure, the study induced seizures in rats once they were a few weeks old, and then compared their hippocampal-dependent spatial learning and memory to that of normal rats.
The first test, a Morris water maze, evaluates two types of memory: working memory and reference memory. Working memory, regulated by the frontal cortex, is measured by the mouse’s ability to find an escape platform in a single testing session. Reference memory is measured by the mouse’s performance in subsequent sessions and is regulated by the hippocampus.
In the water maze test, the rats were placed into a pool at different starting locations and had to locate a platform in order to get out of the water. A comparison of escape times showed that normal rats were significantly faster at reaching the escape platform than rats with seizures, demonstrating the impact of seizures on spatial learning and memory.
At the end of these trials, the rats were placed back into the pool with the platform removed, and the path and time spent in the area where the platform had previously been were recorded. Normal animals spend more time in the quadrant where the platform was because they remember from previous trials. However, unlike the control group rats, the rats with seizures did not display this behavior, indicating a deficit in spatial learning.
The second test, the eight-arm radial-arm water maze, simultaneously assessed working and reference memory and required a greater memory capacity than the first maze. This maze has eight paths or “arms” arranged in a radial pattern around a center. The rats were placed in random arms of the maze and had to find the goal arm containing the escape platform. Entrance into an incorrect arm was considered a reference error, while re-entrance into an incorrect arm was considered a working memory error. The number of reference errors made by the control group and the study group differed significantly while there was little discrepancy for working memory errors, indicating that reference memory is impaired in rats with recurrent seizures.
The neural changes were observed by implanting electrodes directly above the dorsal hippocampus in the rats. The results from the control group and the experimental group differed substantially in the amount of spatial location information conveyed by a single action potential, in the stability of the field, and in the general smoothness and intensity of firing patterns.
This study shows that seizures in rats during early development cause long-term damage in learning, performance, or recall of spatial function related to place cell action potential firing. The poor performance of rats with abnormal place cell firing relates to their impaired spatial performance, as demonstrated in the water maze tasks.
“This is quite remarkable that we can now use single cell action potentials as a biomarker for cognition….While knowing that the hippocampal map is permanently altered following seizures during early development is important, even more important is determining why this occurs,” Holmes explained.
The next step of the research is to study brain rhythms in rats, which Holmes hypothesizes are the cause of the alterations in place cells.