Adult Neurogenesis: Opening the Gates of Troy from the Inside

Commentary The demonstration that new neurons are produced throughout life in mammals—including humans—has generated considerable excitement over the past couple of decades. Evidence of adult-neurogenesis has offered hope that neuronal loss due to injury or neurological disease might one day be repairable. Increased neurogenesis is sought after in most disease fields; however, the epilepsy field stands alone in offering an important note of caution: While neurogenesis in the dentate gyrus of the hippocampus is dramatically increased following a range of epileptogenic injuries, many of these new cells appear to integrate pathologically into the brain, developing aberrant axonal and dendrite projections that underlie the formation of recurrent excitatory connectivity. These observations have led to the hypothesis that aberrant integration of adult-generated neurons may mediate temporal lobe epileptogenesis (1). Numerous lines of evidence have been developed to support this hypothesis. First, the hippocampal dentate gyrus is believed to act as a “gatekeeper,” regulating the flow of excitation through the hippocampal circuit (2). Disruption of this structure, therefore, might be particularly pro-excitatory. Second, the appearance of abnormal granule cells in animal models of temporal lobe epilepsy roughly corresponds to the onset of spontaneous seizures, and abnormal cells are evident in resected human tissue from epilepsy surgeries (3). Finally, genetically manipulating newborn granule cells to induce them to integrate abnormally produces a seizure phenotype, establishing that abnormal cells are capable of causing the disease (4). Abnormal granule cells, therefore, have the ability to open the dentate gate to allow seizures to rampage through the brain. Demonstrating that abnormal granule cells actually contribute to seizure incidence in epilepsy, however, requires additional evidence. To obtain this evidence, Cho and colleagues utilized a transgenic approach to eliminate neurogenesis prior to treating the animals with pilocarpine to induce epileptogenesis. Their hypothesis: If newborn granule cells contribute to epileptogenesis, then blocking neurogenesis should mitigate disease development. The approach selected by the group utilized nestin-δ-HSV-thymidine kinase-EGFP mice. In these animals, the nestin promoter drives thymidine kinase and EGFP expression in neural progenitor cells. This alone does not harm the cells, but treatment of the animals with ganciclovir induces apoptosis among the thymidine–kinase-expressing progenitors. To block neurogenesis, adult animals were treated with ganciclovir for 4 weeks, and then status epilepticus was induced with pilocarpine. Five weeks later, ganciclovir and vehicle-treated animals were video-EEG monitored 24/7 for 2 weeks. Blocking neurogenesis reduced spontaneous seizure frequency by 40%, supporting the hypothesis that these neurons contribute to temporal lobe epileptogenesis. Moreover, seizure frequencies were still reduced in animals examined 1 year after treatment, demonstrating a long-term beneficial effect. Finally, treated animals also exhibited improvement in hippocampal-dependent memory. The presence of abnormal granule cells profoundly alters the hippocampal circuit, so Aberrant Hippocampal Neurogenesis Contributes to Epilepsy and Associated Cognitive Decline.