Suppression of adult neurogenesis increases the acute effects of kainic acid.

Abstract

Adult neurogenesis, the generation of new neurons in the adult brain, occurs in the hippocampal dentate gyrus (DG) and the olfactory bulb (OB) of all mammals, but the functions of these new neurons are not entirely clear. Originally, adult-born neurons were considered to have excitatory effects on the DG network, but recent studies suggest a net inhibitory effect. Therefore, we hypothesized that selective removal of newborn neurons would lead to increased susceptibility to the effects of a convulsant. This hypothesis was tested by evaluating the response to the chemoconvulsant kainic acid (KA) in mice with reduced adult neurogenesis, produced either by focal X-irradiation of the DG, or by pharmacogenetic deletion of dividing radial glial precursors. In the first 4 hrs after KA administration, when mice have the most robust seizures, mice with reduced adult neurogenesis had more severe convulsive seizures, exhibited either as a decreased latency to the first convulsive seizure, greater number of convulsive seizures, or longer convulsive seizures. Nonconvulsive seizures did not appear to change or they decreased. Four-21 hrs after KA injection, mice with reduced adult neurogenesis showed more interictal spikes (IIS) and delayed seizures than controls. Effects were greater when the anticonvulsant ethosuximide was injected 30 min prior to KA administration; ethosuximide allows forebrain seizure activity to be more easily examined in mice by suppressing seizures dominated by the brainstem. These data support the hypothesis that reduction of adult-born neurons increases the susceptibility of the brain to effects of KA.

• Authors: Sloka S Iyengar, John J LaFrancois, Daniel Friedman, Liam J Drew, Christine A Denny, Nesha S Burghardt, Melody V Wu, Jenny Hsieh, René Hen, Helen E Scharfman
• Journal: Experimental neurology (Exp Neurol) Vol. 264 Pg. 135-49 (Feb 2015) ISSN: 1090-2430 [Electronic] United States
• PMID: 25476494 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Anticonvulsants
• Doublecortin Domain Proteins
• Excitatory Amino Acid Agonists
• Glial Fibrillary Acidic Protein
• Microtubule-Associated Proteins
• Neuropeptides
• Ethosuximide
• Thymidine Kinase
• Valganciclovir
• Ganciclovir
• Kainic Acid

Topics

• Animals
• Anticonvulsants (therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Doublecortin Domain Proteins
• Electroencephalography
• Ethosuximide (therapeutic use)
• Excitatory Amino Acid Agonists (pharmacology)
• Ganciclovir (analogs & derivatives, pharmacology)
• Glial Fibrillary Acidic Protein (metabolism)
• Hippocampus (drug effects, pathology)
• Kainic Acid (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Microtubule-Associated Proteins (metabolism)
• Neural Stem Cells (drug effects)
• Neurogenesis (drug effects)
• Neuropeptides (metabolism)
• Seizures (chemically induced, drug therapy, pathology)
• Thymidine Kinase (genetics, metabolism)
• Valganciclovir
• X-Rays