Postnatal neurogenesis as a therapeutic target in temporal lobe epilepsy.
After it was first identified that seizures increase neurogenesis in the adult brain of laboratory animals, the idea that postnatal neurogenesis may be involved in epilepsy became a topic of widespread interest. Since that time, two perspectives have developed. They primarily address temporal lobe epilepsy (TLE), because the data have either been based on animal models of TLE or patients with intractable TLE. The first perspective is that postnatal neurogenesis contributes to the predisposition for seizures in TLE. This premise is founded in the observations showing that there is a dramatic rise in neurogenesis after many types of insults or injuries which ultimately lead to TLE. As a result of the increase in neurogenesis, several changes in the dentate gyrus occur, and the net effect appears to be an increase in excitability. One of the changes is the formation of a population of granule cells (GCs) that mismigrate, leading to ectopic granule cells in the hilus (hilar EGCs) that exhibit periodic bursts of action potentials, and contribute to recurrent excitatory circuitry. Atypical dendrites also form on a subset of GCs, and project into the hilus (hilar basal dendrites). Hilar basal dendrites appear to preferentially increase the glutamatergic input relative to GABAergic synapses, increasing excitability of the subset of GCs that form hilar basal dendrites. The alternate view is that postnatal neurogenesis is a homeostatic mechanism in epilepsy that maintains normal excitability. This idea is supported by studies showing that some of the new GCs that are born after seizures, and migrate into the correct location, have normal or reduced excitability. Here we suggest that both perspectives may be important when considering a therapeutic strategy. It would seem advantageous to limit the numbers of mismigrating GCs and hilar basal dendrites, but maintain normal neurogenesis because it is potentially homeostatic. Maintaining normal neurogenesis is also important because it has been suggested that a decrease in dentate gyrus neurogenesis contributes to depression. It is challenging to design a strategy that would achieve these goals, and it is also difficult to propose how one could administer such a therapy prophylactically, that is, as an "antiepileptogenic" approach. Another issue to address is how a therapeutic intervention with these goals could be successful if it were administered after chronic seizures develop, when most patients seek therapy. Although difficult, a number of approaches are possible, and technical advances suggest that there are more on the horizon.
Center for Dementia Research, The Nathan Kline Institute, 140 Old Orangeburg Rd., Bldg. 35, Orangeburg, NY 10962, United States. hscharfman@nki.rfmh.org
Helen E
HE
Scharfman
Daniel P
DP
McCloskey
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation; D017690:Cell Transplantation; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000473:pathology / Q000517:prevention & control / Q000601:surgery / Q000628:therapy*; D006801:Humans; D007231:Infant, Newborn; D009474:Neurons / Q000502:physiology*; D033581:Stem Cell Transplantation
D000927:Anticonvulsants