Seizures do not appear to be driven by olfactory neurons. Gli1-CreERT2 is expressed in subventricular zone progenitors, which produce neuroblasts and immature neurons that migrate to the olfactory bulb via the rostral migratory stream. Upon arrival in the olfactory bulb, the majority of these cells differentiate into GABAergic olfactory granule cells, while a minority (≈5%) becomes periglomerular cells ( Whitman and Greer, 2009). The processes of these cells are restricted to the olfactory bulb, where they modulate the activity of mitral and tufted cells. The inhibitory phenotype of affected cells, and

a paucity of data linking the olfactory bulb to epileptogenesis, makes these neurons unlikely candidates for producing the seizure phenotype exhibited by www.selleckchem.com/products/Adriamycin.html PTEN KO mice. Several additional lines of evidence support this conclusion. First, mice in which PTEN was selectively deleted from olfactory bulb, but not hippocampus, appeared neurologically normal (although seizure activity

was not assessed) and survived for up to two years in previous studies ( Gregorian et al., 2009). By contrast, PTEN deletion using Cre-driver this website mouse lines that include dentate granule cells among their targets consistently produce a seizure-phenotype and premature death ( Backman et al., 2001; Fraser et al., 2004; Ogawa much et al., 2007; Zhou et al., 2009). Second, the effects of PTEN deletion on olfactory neuron morphology were relatively modest compared to hippocampal granule cells. Finally, simultaneous EEG recordings from hippocampus and olfactory bulb revealed that seizure activity can occur in hippocampus in these animals with no olfactory bulb involvement. The prominent abnormalities exhibited by hippocampal granule cells, the predicted excitatory nature of these abnormalities, the localization of seizures to hippocampus and the comparatively modest effect of PTEN deletion on other cell types strongly favors PTEN KO granule cells as the source of the seizures. The possibility

that PTEN KO cells in other brain regions play some role cannot be entirely excluded. Nonetheless, a pivotal role for PTEN KO hippocampal granule cells is clearly the most parsimonious explanation. Additional studies, perhaps using even more specific gene knockout strategies, may yield more insights in the future. Epileptogenesis in the present study required surprisingly few PTEN KO granule cells (9%–25% of the entire population). Intriguingly, however, key granule cell pathologies in other models of temporal lobe epilepsy also appear to be restricted to a subset of dentate granule cells. Recent studies demonstrate that basal dendrites, hilar ectopic cells and mossy fiber sprouting all result from disruption of newly generated granule cells.