Dentate gyrus progenitor cell proliferation after the onset of spontaneous seizures in the tetanus toxin model of temporal lobe epilepsy

Premysl Jiruska,Anan B.Y Shtaya,David M.S Bodansky,Wei-Chih Chang,William P Gray,John G.R Jefferys

doi:10.1016/j.nbd.2013.02.001

Premysl Jiruska, Anan B.Y Shtaya + Show 4 more

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https://doi.org/10.1016/j.nbd.2013.02.001

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Abstract

Temporal lobe epilepsy alters adult neurogenesis. Existing experimental evidence is mainly from chronic models induced by an initial prolonged status epilepticus associated with substantial cell death. In these models, neurogenesis increases after status epilepticus. To test whether status epilepticus is necessary for this increase, we examined precursor cell proliferation and neurogenesis after the onset of spontaneous seizures in a model of temporal lobe epilepsy induced by unilateral intrahippocampal injection of tetanus toxin, which does not cause status or, in most cases, detectable neuronal loss. We found a 4.5 times increase in BrdU labeling (estimating precursor cells proliferating during the 2nd week after injection of toxin and surviving at least up to 7days) in dentate gyri of both injected and contralateral hippocampi of epileptic rats. Radiotelemetry revealed that the rats experienced 112±24 seizures, lasting 88±11s each, over a period of 8.6±1.3days from the first electrographic seizure. On the first day of seizures, their duration was a median of 103s, and the median interictal period was 23min, confirming the absence of experimentally defined status epilepticus. The total increase in cell proliferation/survival was due to significant population expansions of: radial glial-like precursor cells (type I; 7.2×), non-radial type II/III neural precursors in the dentate gyrus stem cell niche (5.6×), and doublecortin-expressing neuroblasts (5.1×). We conclude that repeated spontaneous brief temporal lobe seizures are sufficient to promote increased hippocampal neurogenesis in the absence of status epilepticus.

Highlights

The generation of new neurons, neurogenesis, in the adult brain continues in mammals, including humans, throughout life (Eriksson et al, 1998; Gage et al, 1998)
Neurogenesis is regulated by a variety of physiological stimuli and newly born dentate gyrus neurons integrate into the circuitry of the adult hippocampus, leading to theories for roles in learning and memory (Deng et al, 2010)
While the majority of rats gain seizure remission in this model after 6–8 weeks, they retain abnormal cellular pathophysiology (Vreugdenhil et al, 2002), permanent cognitive and other behavioral impairments (Brace et al, 1985; Mellanby, 1982), and a minority continues to seize (Mellanby, 1993). This model provides a means of testing the effect of early repeated spontaneous seizures on cell proliferation and neurogenesis independently of prolonged status epilepticus

Summary

Introduction

The generation of new neurons, neurogenesis, in the adult brain continues in mammals, including humans, throughout life (Eriksson et al, 1998; Gage et al, 1998). Hippocampal neurogenesis is affected by a wide range of pathological conditions including of focal epilepsies, in particular those induced by initial status epilepticus (Bender et al, 2003; Bengzon et al, 1997; Gray and Sundstrom, 1998; Jessberger et al, 2005, 2007; Nakagawa et al, 2000; Parent et al, 1997). While the majority of rats gain seizure remission in this model after 6–8 weeks, they retain abnormal cellular pathophysiology (Vreugdenhil et al, 2002), permanent cognitive and other behavioral impairments (Brace et al, 1985; Mellanby, 1982), and a minority continues to seize (Mellanby, 1993) This model provides a means of testing the effect of early repeated spontaneous seizures on cell proliferation and neurogenesis independently of prolonged status epilepticus

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Discussion