The dentate gyrus is hypothesized to function as a “gate,” limiting the flow of excitation through the hippocampus. During epileptogenesis, adult-generated granule cells (DGCs) form aberrant neuronal ...connections with neighboring DGCs, disrupting the dentate gate. Hyperactivation of the mTOR signaling pathway is implicated in driving this aberrant circuit formation. While the presence of abnormal DGCs in epilepsy has been known for decades, direct evidence linking abnormal DGCs to seizures has been lacking. Here, we isolate the effects of abnormal DGCs using a transgenic mouse model to selectively delete PTEN from postnatally generated DGCs. PTEN deletion led to hyperactivation of the mTOR pathway, producing abnormal DGCs morphologically similar to those in epilepsy. Strikingly, animals in which PTEN was deleted from ≥9% of the DGC population developed spontaneous seizures in about 4 weeks, confirming that abnormal DGCs, which are present in both animals and humans with epilepsy, are capable of causing the disease.
► Direct evidence that selective disruption of the dentate gyrus causes epilepsy ► PTEN deletion from as few as 9% of granule cells is sufficient to cause epilepsy ► Findings suggest a plausible mechanism of epileptogenesis
Abnormal hippocampal granule cells are hypothesized to be critical for temporal lobe epileptogenesis, but direct supporting evidence has been limited. Here, Pun and colleagues demonstrate that selective disruption of granule cells by PTEN deletion is sufficient to cause the disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Growing evidence implicates the dentate gyrus in temporal lobe epilepsy (TLE). Dentate granule cells limit the amount of excitatory signaling through the hippocampus and exhibit striking neuroplastic ...changes that may impair this function during epileptogenesis. Furthermore, aberrant integration of newly-generated granule cells underlies the majority of dentate restructuring. Recently, attention has focused on the mammalian target of rapamycin (mTOR) signaling pathway as a potential mediator of epileptogenic change. Systemic administration of the mTOR inhibitor rapamycin has promising therapeutic potential, as it has been shown to reduce seizure frequency and seizure severity in rodent models. Here, we tested whether mTOR signaling facilitates abnormal development of granule cells during epileptogenesis. We also examined dentate inflammation and mossy cell death in the dentate hilus. To determine if mTOR activation is necessary for abnormal granule cell development, transgenic mice that harbored fluorescently-labeled adult-born granule cells were treated with rapamycin following pilocarpine-induced status epilepticus. Systemic rapamycin effectively blocked phosphorylation of S6 protein (a readout of mTOR activity) and reduced granule cell mossy fiber axon sprouting. However, the accumulation of ectopic granule cells and granule cells with aberrant basal dendrites was not significantly reduced. Mossy cell death and reactive astrocytosis were also unaffected. These data suggest that anti-epileptogenic effects of mTOR inhibition may be mediated by mechanisms other than inhibition of these common dentate pathologies. Consistent with this conclusion, rapamycin prevented pathological weight gain in epileptic mice, suggesting that rapamycin might act on central circuits or even peripheral tissues controlling weight gain in epilepsy.
•Rapamycin prevents pathological weight gain in epileptic rodents.•Rapamycin reduces mossy fiber sprouting in epilepsy.•Rapamycin does not block ectopic granule cell accumulation or somatic hypertrophy.•Rapamycin does not block hippocampal inflammatory changes.•Rapamycin does not prevent hilar mossy cell death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Patients with temporal lobe epilepsy are treated with anticonvulsant drugs that neither prevent nor cure the disease. The development of true anti-epileptogenic therapies will require a better ...understanding of the molecular mechanisms of epileptogenesis. Animal and human studies of temporal lobe epilepsy have long implicated newly-born dentate granule cells (DGCs) as mediating many of these epileptogenic changes. Work from our lab described in this report demonstrates that phosphatase and tensin homolog (PTEN) deletion need only occur in up to 25% of hippocampal DGCs to produce a severe epilepsy syndrome in mice. This was the first direct evidence provided to show that abnormal DGCs can cause the disease. It is also conceivable that a certain threshold level of abnormal cells must be reached to provoke epileptogenesis; but after this threshold is passed, additional abnormal cells have no further impact. We hypothesize that the severity of epilepsy is dependent on the number of abnormal DGCs in these animals, and we predict, therefore, that modifying the model to produce fewer abnormal cells will mitigate the disease phenotype . The second chapter, previously published in Neuron, details the selective deletion of PTEN from hippocampal granule cells. The third chapter directly tests our guiding hypothesis, whether deletion from a smaller number of DGCs, roughly 5% or less, is sufficient to cause epilepsy. In the fourth chapter, we will describe initial experiments that test whether and when electroencephalogram (EEG) abnormalities can be reversed by ablating irregular DGCs. These studies will provide novel insights into 1) the role these neurons play in chronic epilepsy, and 2) whether we can identify a therapeutic window to interfere with disease progression.
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