Born to Be Wild: A Case for Targeting Ectopic Adult Born Granule Cells for Seizure Control

Altered Synaptic Drive Onto Birthdated Dentate Granule Cells in Experimental Temporal Lobe Epilepsy Althaus AL, Moore SJ, Zhang H, Du Plummer X, Murphy GG, Parent JM. J Neurosci. 2019;39(38):7604-7614. doi:10.1523/JNEUROSCI.0654-18.2019.Dysregulated adult hippocampal neurogenesis occurs in many temporal lobe epilepsy (TLE) models. Most dentate granule cells (DGCs) generated in response to an epileptic insult develop features that promote increased excitability, including ectopic location, persistent hilar basal dendrites (HBDs), and mossy fiber sprouting. However, some appear to integrate normally and even exhibit reduced excitability compared to other DGCs. To examine the relationship between DGC birthdate, morphology, and network integration in a model of TLE, we retrovirally birth-dated either early-born (postnatal day 7) or adult-born (postnatal day 60) DGCs. Male rats underwent pilocarpine-induced status epilepticus (SE) or sham treatment at postnatal day 56. Three to six months after SE or sham treatment, we used whole-cell patch clamp and fluorescence microscopy to record spontaneous excitatory and inhibitory currents from birth-dated DGCs. We found that both adult-born and early-born populations of DGCs recorded from epileptic rats received increased excitatory input compared with age-matched controls. Interestingly, when adult-born populations were separated into normally integrated (normotopic) and aberrant (ectopic or HBD containing) subpopulations, only the aberrant populations exhibited a relative increase in excitatory input (amplitude, frequency, and charge transfer). The ratio of excitatory to inhibitory input was most dramatically upregulated for ectopically localized DGCs. These data provide definitive physiological evidence that aberrant integration of post-SE, adult-born DGCs contributes to increased synaptic drive and supports the idea that ectopic DGCs serve as putative hub cells to promote seizures.Significance Statement:Adult DGC neurogenesis is altered in rodent models of TLE. Some of the new neurons show abnormal morphology and integration, but whether adult-generated DGCs contribute to the development of epilepsy is controversial. We examined the synaptic inputs of age-defined populations of DGCs using electrophysiological recordings and fluorescent retroviral reporter birth-dating. Dentate granule cells generated neonatally were compared with those generated in adulthood, and adult-born neurons with normal versus aberrant morphology or integration were examined. We found that adult-born, ectopically located DGCs exhibit the most pro-excitatory physiological changes, implicating this population in seizure generation or progression. Targeting Seizure-Induced Neurogenesis in a Clinically Relevant Time Period Leads to Transient But Not Persistent Seizure Reduction Varma P, Brulet R, Zhang L, Hsieh J. J Neurosci. 2019;39(35):7019-7028. doi:10.1523/JNEUROSCI.0920-19.2019.Mesial temporal lobe epilepsy (mTLE), the most common form of medically refractory epilepsy in adults, is usually associated with hippocampal pathophysiology. Using rodent models of mTLE, many studies including work from our laboratory have shown that new neurons born around the onset of severe acute seizures known as status epilepticus (SE) are crucial for the process of epileptogenesis and targeting seizure-induced neurogenesis either genetically or pharmacologically can impact the frequency of chronic seizures. However, these studies are limited in their clinical relevance as none of them determines the potential of blocking new neurons generated after the epileptogenic insult to alleviate the development of chronic seizures. Therefore, using a pilocarpine-induced SE model of mTLE in mice of either sex, we show that >4 weeks of continuous and concurrent ablation of seizure-induced neurogenesis after SE can reduce the formation of spontaneous recurrent seizures by 65%. We also found that blocking post-SE neurogenesis does not lead to long-term seizure reduction as the effect was observed only transiently for 10 days with >4 weeks of continuous and concurrent ablation of seizure-induced neurogenesis. Thus, these findings provide evidence that seizure-induced neurogenesis when adequately reduced in a clinically relevant time period has the potential to transiently suppress recurrent seizures, but additional mechanisms need to be targeted to permanently prevent epilepsy development.Significance Statement:Consistent with morphological and electrophysiological studies suggesting aberrant adult-generated neurons contribute to epilepsy development, ablation of seizure-induced new neurons at the time of the initial insult reduces the frequency of recurrent seizures. In this study, we show that continuous targeting of post-insult new neurons in a therapeutically relevant time period reduces chronic seizures; however, this effect does not persist suggesting possible additional mechanisms.