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Invasion of the CA2 Region

How sprouting mossy fibers might contribute to epileptic activity

A previously undiscovered mechanism in the hippocampus might contribute to epileptic activity. In mesial temporal lobe epilepsy (MTLE), as Ute Häussler and colleagues at the University Hospital Freiburg and the IMTEK Freiburg have discovered, a specific region in the hippocampus experiences a sprouting of mossy fibers while its neighboring regions are in retreat. In the healthy hippocampus, these mossy fibers make synaptic transmissions to one neighboring region. However, in MTLE, the destination of their synaptic output is still under investigation.

In the case of a loss of certain regions in the neuronal network, as most commonly seen in neurodegenerative diseases like Alzheimer’s, Huntington’s, and epilepsy, the human brain conveys its resilience in several mechanisms by trying to compensate for the loss of neuronal regions. This mechanism can be compared to a power grid, in which other power plants have to compensate for the loss of one power plant, and where a fallout in a whole area will sometimes have to be bypassed to save the grid as a whole. But as Ute Häussler hypothesizes in her publication “Mossy Fiber Sprouting and Pyramidal Cell Dispersion in the Hippocampal CA2 Region in a Mouse Model of Temporal Lobe Epilepsy”, it might just be one such mechanism that may contribute to some aspects of epileptic activity.
The CA2 region of the hippocampus, the region of the brain most frequently associated with inhibition, memory, and space, is extraordinary in many respects. In MTLE, its neighboring regions known as CA1 and CA3 experience a dramatic loss of their cells and which leaves behind only a handful of deformed cells, while the CA2 cells survive. “The pyramidal cells of the CA2 region have some extraordinary properties. They seem to be less excitable and are difficult to potentiate in the healthy hippocampus. But we do not really know yet why they survive in epilepsy”, Häussler says. “What we observed in our mouse model for temporal lobe epilepsy, however, was that the CA2 region was significantly elongated and that mossy fibers were heavily invading the cellular layers of the region instead of only projecting to the dendritic layers”, the neuroscientist adds. In a healthy state, the dendritic layer can be compared to a lightning arrester which helps to control incoming impulses, whereas this function seems compromised in MTLE. “Such a change from dendritic excitation, that leaves options for activity modulation, to direct somatic excitation, together with a decrease in inhibition might act like a flashpoint. This results in temporary explosions: the epileptic seizures.”
Unusual Properties of Mossy Fibers
Mossy fibers are a specific type of axon, the long, slender projection of a neuron, which, like an antenna, conduct electrical impulses away from the cell body of the neuron. In the hippocampus, these fibers are a crucial part of a relay that is known as the hippocampal loop. This loop processes activity from the entorhinal cortex. Mossy fibers have unusual properties that leave room for hypothesis: “These mossy fibers have different types of synapses depending on the target region”, Häussler adds.
Häussler and her team are now trying to find out how this activity transmission in CA2 is changed in epilepsy and which factors change in MTLE in such a way that mossy fibers start to sprout in this region. “We have not yet identified the underlying mechanism that can explain this sprouting. We only know that these mossy fibers tend to sprout as soon as they lose their target cells.” Häussler emphasizes that there is not only mossy fiber sprouting to CA2, but there is also an intrinsic mossy fiber sprouting within the dentate gyrus, the hippocampal region that contributes to the formation of memories. “Through their mossy fibers, granule cells couple themselves or to their immediate neighbors, and there is a recurrence in this dynamic, which also only develops in epilepsy.”
Potential Treatment in Stimulation of Altered Network
Häussler now wants to consider the altered structure of CA2 in higher resolution. “We know where the CA2 cells get their input from but we do not know where they send their output to. Normally CA2 projects to CA1 within the same level, but CA1 is gone in temporal lobe epilepsy. We also want to find out why these specific CA2 cells survive.” If some of the mechanisms behind this dynamic could be identified, this may lead to potential treatments for early stages of MTLE before all the other cells are lost. “We might even be able to preserve larger parts of the network and maintain a certain level of functionality”, Häussler adds.
Defining the integration of the CA2 region and where it projects to will also help the researchers to understand its network dynamic and how it changes in MTLE. In her research, Häussler sees specific potential for new treatments involving stimulation: “We can imagine ways to stimulate this region as one part of the altered network and to find stimulation parameters that block the propagation of epileptic activity within and outside the hippocampus. 

Original Publication
Image caption:
A mouse model of temporal lobe epilepsy conveys the sprouting of mossy fibers and dispersion of pyramidal cells in the CA2 region of the hippocampus


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