Abstracts

Rationale: Adult generated hippocampal dentate granule cells have been implicated in the development of epilepsy. Following an epileptogenic brain insult, these cells integrate abnormally, leading to characteristic pathologies of the epileptic brain, including the appearance of ectopic cells, cells with aberrant basal dendrites and mossy fiber sprouting. Recurrent excitatory circuits created by these pathologies are hypothesized to promote hyperexcitability and seizures. Direct evidence in support of this hypothesis, however, is limited. Methods: Here, we sought to determine whether abnormal granule cells are sufficient to cause epilepsy. Using conditional, inducible triple-transgenic Gli1-CreERT2 X PTENflox/flox X GFP reporter mice we were able to selectively disrupt the development of postnatally generated neurons. Triple transgenic animals were treated with tamoxifen on P14, leading to the deletion of PTEN (phosphatase and tensin homologue) and activation of GFP expression in a subset of subgranular and subventricular zone progenitors. Results: PTEN deletion was highly selective, with a subset of granule cells and olfactory neurons being the only neuronal populations affected in the CNS. PTEN deletion from granule cells reproduced key abnormalities of the epileptic brain, including formation of basal dendrites, ectopic migration to the hilus, and mossy fiber sprouting. Acute hippocampal slices prepared from PTEN deleted animals revealed hyperexcitability in this region. Moreover, animals exhibited longer evoked seizures when challenged with flurothyl. Finally, 24/7 video-EEG monitoring confirmed that these animals were spontaneously epileptic, exhibiting frequent seizures by three months of age. Conclusions: Abnormal granule cells are a hallmark of temporal lobe epilepsy, and are present in both epileptic animals and humans. For decades, it has been unclear whether these abnormal cells are a cause or consequence of epilepsy. The present study provides new evidence indicating that disruption of postnatally generated neurons is capable of causing epilepsy, and morphological and physiological data strongly implicates hippocampal granule cells, rather than olfactory neurons, in this process. Future studies will focus on determining whether these cells are necessary for epileptogenesis.