Hippocampal granule cells generated in the weeks before and after an epileptogenic brain injury can integrate abnormally into the dentate gyrus, potentially mediating temporal lobe epileptogenesis. Previous studies have demonstrated that inhibiting granule cell production before an epileptogenic brain insult can mitigate epileptogenesis. Here, we extend upon these findings by ablating newly generated cells after the epileptogenic insult using a conditional, inducible diphtheria-toxin receptor expression strategy in mice. Diphtheria-toxin receptor expression was induced among granule cells born up to 5 weeks before pilocarpine-induced status epilepticus and these cells were then eliminated beginning 3 d after the epileptogenic injury. This treatment produced a 50% reduction in seizure frequency, but also a 20% increase in seizure duration, when the animals were examined 2 months later. These findings provide the first proof-of-concept data demonstrating that granule cell ablation therapy applied at a clinically relevant time point after injury can have disease-modifying effects in epilepsy.

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.

Aberrant integration of newborn hippocampal granule cells is hypothesized to contribute to the development of temporal lobe epilepsy. To test this hypothesis, we used a diphtheria toxin receptor expression system to selectively ablate these cells from the epileptic mouse brain. Epileptogenesis was initiated using the pilocarpine status epilepticus model in male and female mice. Continuous EEG monitoring was begun 2–3 months after pilocarpine treatment. Four weeks into the EEG recording period, at a time when spontaneous seizures were frequent, mice were treated with diphtheria toxin to ablate peri-insult generated newborn granule cells, which were born in the weeks just before and after pilocarpine treatment. EEG monitoring continued for another month after cell ablation. Ablation halted epilepsy progression relative to untreated epileptic mice; the latter showing a significant and dramatic 300% increase in seizure frequency. This increase was prevented in treated mice. Ablation did not, however, cause an immediate reduction in seizures, suggesting that peri-insult generated cells mediate epileptogenesis, but that seizures per se are initiated elsewhere in the circuit. These findings demonstrate that targeted ablation of newborn granule cells can produce a striking improvement in disease course, and that the treatment can be effective when applied months after disease onset.

When mice actively locomote, visual signals in their primary visual cortex (V1) are strongly modulated[1]. This observation has fundamentally altered conceptions of a brain region previously assumed to be a passive image processor, and extensive work has followed, aimed at dissecting the sources, recipients, and functional consequences of running-correlated modulation [2-13]. However, it remains unclear whether visual processing in primates might similarly change during active locomotion. We therefore measured V1 activity in a nonhuman primate, the common marmoset (Callithrix jacchus), while they alternated between running and stationary. In contrast to the often large increases in mouse V1 during running, conventional metrics of response in marmoset V1 were barely distinguishable during running versus not running, with some slight decreases evident. However, by leveraging large-scale recordings, analysis of the latent variables driving population activity revealed a common mechanism in both species: trial-to-trial fluctuations of shared gain modulations were present across V1 in mice and marmosets. These gain modulations were larger in mice and were often positively correlated with running; they were smaller and more likely to be weakly negatively correlated with running in marmosets. Thus, population-scale gain fluctuations of V1 reflect a common principle of mammalian visual cortical function, but there are important quantitative differences in their magnitudes and correlations with behavior that yield distinct consequences for the relation between vision and action in primates versus rodents.

When mice run, activity in their primary visual cortex (V1) is strongly modulated. This observation has altered conception of a brain region assumed to be a passive image processor. Extensive work has followed to dissect the circuits and functions of running-correlated modulation. However, it remains unclear whether visual processing in primates might similarly change during locomotion. We measured V1 activity in marmosets while they viewed stimuli on a treadmill. In contrast to mouse V1, marmoset V1 was slightly but reliably suppressed during running. Population-level analyses revealed trial-to-trial fluctuations of shared gain across V1 in both species, but these gain modulations were smaller and more often negatively correlated with running in marmosets. Thus, population-scale gain fluctuations of V1 reflect a common feature of mammalian visual cortical function, but important quantitative differences yield distinct consequences for the relation between vision and action in primates versus rodents.