Abstracts

Rationale: Aberrantly-interconnected granule cells are characteristic of temporal lobe epilepsy. By reducing network stability, these abnormal neurons may contribute directly to disease development. Only subsets of granule cells, however, exhibit abnormalities. Why this is the case is not known. Ongoing neurogenesis in the adult hippocampus may provide an explanation. Newly-generated granule cells may be uniquely vulnerable to environmental disruptions relative to their mature neighbors. Here, we determine whether there is a critical period following neuronal birth, during which neuronal integration can be disrupted by an epileptogenic insult. We predict that immature and newborn granule cells -- but not mature ones -- will develop aberrant connections during epileptogenesis. Methods: To establish the age and reveal the morphology of mature, immature and newborn granule cells, BrdU was given to Thy1-GFP-expressing transgenic mice eight weeks before (mature), one week before (immature) or three weeks after (newborn) pilocarpine-induced epileptogenesis. The neuronal morphology of the subset of dentate granule cells labeled with both BrdU and GFP was examined both four and eight weeks after pilocarpine treatment (when all cells were mature) using confocal microscopy. Dendritic orientation, branching pattern, spine density and neuronal position were assessed.Results: Almost 50% of immature granule cells exposed to pilocarpine-induced epileptogenesis exhibited aberrant hilar basal dendrites. In contrast, only 9% of mature granule cells exposed to the identical insult possessed basal dendrites. In addition, newborn cells were even more severely impacted than immature cells, with 40% exhibiting basal dendrites and an additional 20% exhibiting migration defects. By comparison, less than 5% of neurons from normal animals exhibited either abnormality, regardless of age.Conclusions: Together, these data demonstrate the existence of a critical period following the birth of adult-generated neurons during which they are vulnerable to being recruited into epileptogenic neuronal circuits. Pathological brain states, therefore, may pose a significant hurdle for the appropriate integration of newly-born endogenous (and exogenously implanted) neurons. Moreover, thousands of new neurons are added to the brain in the weeks after epileptogenesis, and, disturbingly, our findings indicate that the majority of these cells integrate abnormally. Abnormal integration of such large numbers of neurons may contribute to the development of epilepsy, and/or to co-morbid conditions associated with epilepsy, such as cognitive impairment and depression.