Abstract
Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.
Highlights
Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment
Past reports using nonspecific pharmacological agents suggest that inhibiting adult hippocampal neurogenesis after acute seizures leads to reduced seizures[13,14], while other studies indicate that blocking adult neurogenesis via low-dose irradiation does not alter the stepwise progression of kindling[15] or even slightly accelerated it[16]
Using a genetic approach to inducibly suppress adult neurogenesis, we show that the ablation of neurogenesis before acute seizures reduces chronic seizure frequency, but does not completely impede epilepsy development
Summary
Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. The effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult. Pharmacological modulation of seizure-induced hippocampal neurogenesis by valproic acid (VPA) or endoneuraminidase restored hippocampal-dependent memory function[27,28] While these studies are consistent with the involvement of adultgenerated neurons in epilepsy-associated cognitive function, these drugs may have other cellular targets that contribute to the behavioural changes in epileptic animals. More selective manipulation of adult neurogenesis is warranted to link adultgenerated neurons with epilepsy-associated cognitive function
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