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The Journal of Neuroscience, July 11, 2007, 27(28):7541-7552; doi:10.1523/JNEUROSCI.0431-07.2007

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Development/Plasticity/Repair
Pilocarpine-Induced Seizures Cause Selective Time-Dependent Changes to Adult-Generated Hippocampal Dentate Granule Cells

Cynthia Walter,¹ Brian L. Murphy,^1,3 Raymund Y. K. Pun,¹ Anne L. Spieles-Engemann,³ and Steve C. Danzer^1,2,3

¹Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, ²Departments of Anesthesia and Pediatrics, University of Cincinnati, Cincinnati, Ohio 45221, and ³Program in Neuroscience, University of Cincinnati, Cincinnati, Ohio 45229

Correspondence should be addressed to Dr. Steve C. Danzer, 3333 Burnet Avenue, ML 2001, Cincinnati, OH 45229-3039. Email: steve.danzer{at}cchmc.org

Aberrantly interconnected granule cells are characteristic of temporal lobe epilepsy. By reducing network stability, these abnormal neurons may contribute directly to disease development. Only subsets of granule cells, however, exhibit abnormalities. Why this is the case is not known. Ongoing neurogenesis in the adult hippocampus may provide an explanation. Newly generated granule cells may be uniquely vulnerable to environmental disruptions relative to their mature neighbors. Here, we determine whether there is a critical period after neuronal birth during which neuronal integration can be disrupted by an epileptogenic insult. By bromodeoxyuridine birthdating cells in green fluorescent protein-expressing transgenic mice, we were able to noninvasively label granule cells born 8 weeks before (mature), 1 week before (immature), or 3 weeks after (newborn) pilocarpine-epileptogenesis. Neuronal morphology was examined 4 and 8 weeks after pilocarpine treatment. Strikingly, almost 50% of immature granule cells exposed to pilocarpine-epileptogenesis exhibited aberrant hilar basal dendrites. In contrast, only 9% of mature granule cells exposed to the identical insult possessed basal dendrites. Moreover, newborn cells were even more severely impacted than immature cells, with 40% exhibiting basal dendrites and an additional 20% exhibiting migration defects. In comparison, <5% of neurons from normal animals exhibited either abnormality, regardless of age. Together, these data demonstrate the existence of a critical period after the birth of adult-generated neurons during which they are vulnerable to being recruited into epileptogenic neuronal circuits. Pathological brain states therefore may pose a significant hurdle for the appropriate integration of newly born endogenous, and exogenous, neurons.

Key words: basal dendrites; dentate gyrus; epilepsy; migration; neurogenesis; transplantation

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Received Jan. 30, 2007; revised May 1, 2007; accepted June 5, 2007.

Correspondence should be addressed to Dr. Steve C. Danzer, 3333 Burnet Avenue, ML 2001, Cincinnati, OH 45229-3039. Email: steve.danzer{at}cchmc.org

This article has been cited by other articles:

				R. J. Morgan and I. Soltesz From the Cover: Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures PNAS, April 22, 2008; 105(16): 6179 - 6184. [Abstract] [Full Text] [PDF]

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