Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline

Kyung-Ok Cho; Zane R Lybrand; Naoki Ito; Rebecca Brulet; Farrah Tafacory; Ling Zhang; Levi Good; Kerstin Ure; Steven G Kernie; Shari G Birnbaum; Helen E Scharfman; Amelia J Eisch; Jenny Hsieh

doi:10.1038/ncomms7606

Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline

Nat Commun. 2015 Mar 26:6:6606. doi: 10.1038/ncomms7606.

Authors

Affiliations

¹ 1] Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pharmacology, School of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
² Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
³ 1] Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Clinical Research, Oriental Medicine Research Center, Kitasato University, Tokyo 108-8641, Japan.
⁴ Department of Neurology &Neurotherapeutics, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
⁵ Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Baylor College of Medicine, Houston, Texas 77030, USA.
⁶ Department of Pediatrics, Columbia University, New York, New York 10027, USA.
⁷ Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
⁸ The Nathan Kline Institute for Psychiatric Research and NYU Langone Medical Center, Orangeburg, New York 10962, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / metabolism
Cognition Disorders / chemically induced
Cognition Disorders / etiology
Cognition Disorders / physiopathology*
Disease Models, Animal
Doublecortin Domain Proteins
Epilepsy / chemically induced
Epilepsy / complications
Epilepsy / physiopathology
Epilepsy, Temporal Lobe / chemically induced
Epilepsy, Temporal Lobe / complications
Epilepsy, Temporal Lobe / physiopathology*
Hippocampus / growth & development*
Hippocampus / metabolism
Hippocampus / physiopathology
Immunohistochemistry
Mice
Mice, Transgenic
Microtubule-Associated Proteins / metabolism
Muscarinic Agonists / toxicity
Nerve Tissue Proteins / metabolism
Neural Stem Cells
Neurogenesis / genetics*
Neurogenesis / physiology
Neurons / metabolism
Neuropeptides / metabolism
Pilocarpine / toxicity

Substances

Basic Helix-Loop-Helix Transcription Factors
Doublecortin Domain Proteins
Microtubule-Associated Proteins
Muscarinic Agonists
Nerve Tissue Proteins
Neuropeptides
Pilocarpine
Neurogenic differentiation factor 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding