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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 phos-phatase 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 knockout mice. Remarkably, epilepsy occurred in almost all of the PTEN knockout mice within 4-6 weeks of inducing the PTEN inac-tivation. As documented by intracranial EEG recordings, the seizures appeared to originate focally within the hippocam-pus, 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 th...

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UBE2A deficiency syndrome (also known as X-linked intellectual disability type Nascimento) is an intellectual disability syndrome characterized by prominent dysmorphic features, impaired speech and often epilepsy. The syndrome is caused by Xq24 deletions encompassing the UBE2A (HR6A) gene or by intragenic UBE2A mutations. UBE2A encodes an E2 ubiquitin-conjugating enzyme involved in DNA repair and female fertility. A recent study in Drosophila showed that dUBE2A binds to the E3 ligase Parkin, which is required for mitochondrial function and responsible for juvenile Parkinson's disease. In addition, these studies showed impairments in synaptic transmission in dUBE2A mutant flies. However, a causal role of UBE2A in of cognitive deficits has not yet been established. Here, we show that Ube2a knockout mice have a major deficit in spatial learning tasks, whereas other tested phenotypes, including epilepsy and motor coordination, were normal. Results from electrophysiological measurements in the hippocampus showed no deficits in synaptic transmission nor in the ability to induce long-term synaptic potentiation. However, a small but significant deficit was observed in mGLUR-dependent long-term depression, a pathway previously implied in several other mouse models for neurodevelopmental disorders. Our results indicate a causal role of UBE2A in learning and mGLUR-dependent long-term depression, and further indicate that the Ube2a knockout mouse is a good model to study the molecular mechanisms underlying UBE2A deficiency syndrome.

Target of rapamycin complex 1 (TORC1) is an important regulator of neuronal function. However, whereas a modest activation of the TORC1 signaling pathway has been shown to affect synaptic plasticity, learning and memory, the effect of TORC1 hypo-activation is less clear. This knowledge is particularly important since TORC1 inhibitors may hold great promise for treating a variety of disorders, including developmental disorders, aging-related disorders, epilepsy and cancer. Such treatments are likely to be long lasting and could involve treating young children. Hence, it is pivotal that the effects of sustained TORC1 inhibition on brain development and cognitive function are determined. Here, we made use of constitutive and conditional Rheb1 mutant mice to study the effect of prolonged and specific reduction in the TORC1 pathway. We show that Rheb1 mutant mice show up to 75% reduction in TORC1 signaling, but develop normally and show intact synaptic plasticity and hippocampus-dependent learning and memory. We discuss our findings in light of current literature in which the effect of pharmacological inhibition of TORC1 is studied in the context of synaptic plasticity and learning. We conclude that in contrast to TORC1 hyper-activity, cognitive function is not very sensitive to sustained and specific down-regulation of TORC1 activity.