“TOR”-ing down the Dentate Gate in Temporal Lobe Epilepsy

Commentary The dentate gyrus (DG) is thought to serve as a gate regulating the spread of excitatory input from the entorhinal cortex into the hippocampus (1). Breakdown of this gating function in the DG has been hypothesized to promote development of epileptogenesis in temporal lobe epilepsy (1, 2). A variety of pathological changes in DG granule cells in animal models and patients with temporal lobe epilepsy may contribute to disrupted DG function, including somatic hypertrophy, formation of basilar dendrites, ectopic granule cells within the hilus, and mossy fiber sprouting (3). These and other cellular and molecular abnormalities within the DG may lead to the formation of aberrant, excitatory circuits that result in temporal lobe epilepsy. However, as previous studies linking DG dysfunction and epileptogenesis have primarily been correlative in nature, direct proof that such DG abnormalities can definitively cause temporal lobe epilepsy has been lacking. In an elegant but conceptually straightforward study, Pun and colleagues provide compelling evidence that pathological disruption of the dentate gyrus is capable of causing temporal lobe epilepsy. To test this longstanding hypothesis, they took advantage of a specific genetic manipulation involving activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway within DG granule cells. The mTORC1 pathway regulates a number of important cellular processes and has been implicated in promoting epileptogenesis in a variety of types of epilepsy (4). This is especially well-established in animal models of the genetic epilepsy, tuberous sclerosis complex; however, there is also some evidence for a role of mTORC1 in models of acquired epilepsy, such as due to brain injury following status epilepticus or trauma. Using targeted genetic techniques, Pun and colleagues inactivated the phosphatase and tensin homolog (PTEN) gene primarily in DG granule cells in 2-week-old mice, as well as incidentally in a small population of inhibitory interneurons in the olfactory bulb. As PTEN acts as an upstream regulator of the mTORC1 pathway, loss of PTEN led to abnormal hyperactivation of the mTORC1 pathway in the targeted neurons of the knock-out mice. Remarkably, epilepsy occurred in almost all of the PTEN knock-out mice within 4–6 weeks of inducing the PTEN inactivation. As documented by intracranial EEG recordings, the seizures appeared to originate focally within the hippocampus, not neocortex. Quantitative assessment found that PTEN inactivation in as few as 9% of DG granule cells was enough to cause epilepsy. Furthermore, the DG granule cells in these mice developed a number of pathological abnormalities seen in human patients and other animal models of temporal lobe epilepsy, including neuronal hypertrophy, basal dendrite formation, increased dendritic spine density, ectopic neurons, and mossy fiber sprouting. Importantly, treatment with the mTORC1 inhibitor, rapamycin, significantly attenuated the development of epilepsy and DG pathological changes, indicating that abnormal mTORC1 pathway activation mediated epileptogenesis in the PTEN knock-out mice. Thus, this study provides direct evidence that mTOR-mediated pathological abnormalities in DG granule cells are sufficient to cause temporal lobe epilepsy. Given the potential significance of this finding, this study was thorough in including a number of control experiments to evaluate for alternative interpretations and mechanisms. The incidental inactivation of PTEN in inhibitory granule cells in Excessive Activation of mTOR in Postnatally Generated Granule Cells Is Sufficient to Cause Epilepsy.