(2012) crossed a Gli1-CreERT2 mouse line with floxed Pten and GFP recombination reporter mice. Because the hippocampal dentate gyrus is one of the few adult brain regions wherein neural progenitors persist postnatally, tamoxifen treatment of the mice beginning at postnatal day 14, along with inefficient Cre-mediated recombination, enabled relatively specific Pten knockout in a minority

of DGCs. They found that loss of PTEN and the subsequent increase in mTOR signaling induced profound abnormalities in DGC morphology that recapitulate those seen in TLE. Affected DGCs displayed neuronal hypertrophy, abnormal basal dendrites, dramatically increased dendritic spine density, and ectopic locations Galunisertib nmr ( Figure 1C). In 82% of animals, Pten deletion led to spontaneous seizures beginning as early as 4 weeks GSK2656157 after tamoxifen treatment and increasing in severity over time. By correlating the degree of recombination with the presence of an epilepsy phenotype, they observed that Pten deletion in as few as 9% of DGCs was sufficient to induce epilepsy. Because Gli1 is expressed in subgranular

and subventricular zone neural progenitors, as well as in subsets of glia, it was important to exclude these as a source of epileptogenic plasticity. No morphological changes were observed in the very small subset of glia (less than 3% in the densest region) that underwent recombination. In addition, alterations due to Pten deletion were much less robust in the olfactory bulb than the dentate gyrus. More importantly, Pun et al. (2012) recorded EEG simultaneously from the hippocampus and olfactory bulb and found that seizure onsets occurred in the hippocampus without any corresponding activity in the bulb. They also confirmed that the pathological effects of Pten deletion were mediated via mTOR activation by blocking GBA3 them with

rapamycin, an mTOR inhibitor. Rapamycin treatment prevented epilepsy development in three animals and decreased seizure frequency by more than ten-fold in two others. The treatment also abolished mossy fiber sprouting, but the importance of this effect for attenuating seizures is uncertain given that others have found rapamycin treatment produces transitory effects, and the degree of sprouting does not correlate well with seizure reduction ( Buckmaster and Lew, 2011). Interestingly, Pun et al. (2012) found that some DGCs that sprout do not show evidence of recombination, suggesting that mossy fiber sprouting may be a consequence of seizures, rather than a cause. The proximate cause of epilepsy in this model is, of course, the elimination of PTEN from a subset of postnatally generated neurons. Although this induces profound abnormalities in a minority of DGCs, it is not clear how these abnormalities specifically relate to epileptogenesis.