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Exp Neurol. 2015 Feb;264:135-49. doi: 10.1016/j.expneurol.2014.11.009. Epub 2014 Dec 2.

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

Author information

1
Center for Dementia Research, The Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962.
2
Department of Neurology, New York University Langone Medical Center, New York, NY 10016.
3
WIBR, University College of London, London, UK WC1E 6BT.
4
Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY 10032.
5
Department of Psychology, Hunter College, City University of New York, New York, NY 10065.
6
Department of Molecular Neurobiology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
7
Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY 10032; Department of Molecular Neurobiology, University of Texas Southwestern Medical Center, Dallas, TX 75390; New York State Psychiatric Institute, New York, NY 10032.
8
Center for Dementia Research, The Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962; Departments of Child & Adolescent Psychiatry, Physiology & Neuroscience, and Psychiatry, New York University Langone Medical Center, New York, NY 10016. Electronic address: hscharfman@nki.rfmh.org.

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.

KEYWORDS:

convulsive seizures; dentate gyrus; electroencephalography (EEG); epilepsy; hippocampus; inhibition; interictal spikes (IIS); subgranular zone (SGZ)

PMID:
25476494
PMCID:
PMC4800819
DOI:
10.1016/j.expneurol.2014.11.009
[Indexed for MEDLINE]
Free PMC Article

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