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Targeting Newly Generated Granule Cells: A Double-Edged Sword

Commentary Until the turn of the century, it was believed that neurogenesis did not occur in adult brains. Now, it is well established that adult neurogenesis does occur, albeit in specific brain areas. In the hippocampus, newly generated granule cells are produced by neural progenitor cells in the subgranular zone. In the healthy brain, these cells then migrate to the granule cell layer of the dentate gyrus, where they project dendrites into the molecular layer and axons into the hilus and CA3. It is believed that these adult-born granule cells play an important role in learning and memory. Specifically, scientists have hypothesized that new-born neurons are engaged in new episodes of learning in order to reduce memory interference, thereby aiding in pattern separation and encoding of temporal contexts (1). There is little doubt that adult neurogenesis serves an important and beneficial purpose in the healthy brain. However, in an epileptic brain, adult neurogenesis can stop being merely beneficial and may actually contribute to the epileptogenic process (2). A critical time window exists where immature and newborn granule cells are vulnerable to aberrant seizure-induced plasticity. An epileptogenic insult can induce newly generated granule cells to develop aberrant dendritic projections (hilar basal dendrites) and axonal projections (mossy fiber sprouting) (3). In addition, cells born after the insult can ectopically migrate and integrate improperly into the hilus (Figure 1). Together, these abnormalities are hypothesized to contribute to a breakdown of the dentate gate, the formation of recurrent excitatory loops in the hippocampus, and temporal lobe epileptogenesis (4). As such, blocking neurogenesis may actually be beneficial for treating epilepsy. Previously, Jung et al. (5) blocked neurogenesis through infusion of an antimitotic agent from 1 day before to 14 days after the epileptogenic insult and observed decreases in seizure frequency and duration. In a different study, Cho et al. (6) demonstrated that ablating granule cell progenitors 4 weeks before an epileptogenic insult resulted in a long-term reduction in seizure frequency but had no effect on seizure duration (Figure 1). To achieve a more complete ablation, Cho et al. also experimented with actively ablating granule cell progenitors 4 weeks before and again 4 weeks after the epileptogenic insult. This double-hit ablation strategy was expected to improve seizure attenuation, but instead, no significant seizure reduction was observed. The authors suggested that this may be a result of the second hit Ablation of Newly Generated Hippocampal Granule Cells Has Disease-Modifying Effects in Epilepsy.