Long-term genetic fate mapping of adult generated neurons in a mouse temporal lobe epilepsy model.

In the epileptic brain, seizures can increase hippocampal neurogenesis, while opposingly seizure-associated brain pathology has been shown to detrimentally affect neurogenesis. The long-term impact of recurrent seizures on the number of new neurons as well as their relative contribution to the granule cell layer remains an open question. Therefore we analyzed neuron addition based on genetic fate mapping in a chronic model of epilepsy comparing non-kindled animals and kindled animals having at least one generalized seizure with and without further seizures. The number of all new granule cells added to the dentate gyrus following the onset of kindling was significantly increased (7.0-8.9 fold) in kindled groups. The hyperexcitable kindled state and a prior seizure history proved to be sufficient to cause a pronounced long-term net effect on neuron addition. An ongoing continuous occurrence of seizures did not further increase the number of new granule cells in the long-term. In contrast, a correlation was found between the cumulative duration of seizures and neuron addition following a kindled state. In addition, the overall number of seizures influenced the relative portion of new cells among all granule cells. Non-kindled animals showed 1.6% of new granule cells among all granular cells by the end of the experiment. This portion reached 5.7% in the animals which experienced either 10 or 22 seizures. A percentage of 8.4% new cells were determined in the group receiving 46 seizures which is a significant increase in comparison to the control group. In conclusion, permanent genetic fate mapping analysis demonstrated that recurrent seizures result in a lasting change in the makeup of the granule cell layer with alterations in the relative contribution of newborn neurons to the granule cell network. Interestingly, the formation of a hyperexcitable kindled network even without recent seizure activity can result in pronounced long-term alterations in the absolute number of new granule cells. However, seizure density also seems to play a critical role with more frequent seizures resulting in increased fractions of new neurons.