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A neuroprotective role for polyamines in a Xenopus tadpole model of epilepsy

Nature Neuroscience volume 14, pages 505–512 (2011)Cite this article

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Abstract

Polyamines are endogenous molecules involved in cell damage following neurological insults, although it is unclear whether polyamines reduce or exacerbate this damage. We used a developmental seizure model in which we exposed Xenopus laevis tadpoles to pentylenetetrazole (PTZ), a known convulsant. We found that, after an initial PTZ exposure, seizure onset times were delayed in response to a second PTZ exposure 4 h later. This protective effect was a result of activity-dependent increases in synthesis of putrescine, the simplest polyamine. Unlike more complex polyamines that directly modulate ion channels, putrescine exerted its effect by altering the balance of excitation to inhibition. Tectal neuron recordings, 4 h after the initial seizure, revealed an elevated frequency of GABAergic spontaneous inhibitory postsynaptic currents. Our data suggest that this effect is mediated by an atypical pathway that converts putrescine into GABA, which then activates presynaptic GABAB receptors. Our data suggest that polyamines have a previously unknown neuroprotective role in the developing brain.

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Figure 1: PTZ-induced seizures alter the onset latency of subsequent seizures.
Figure 2: Increases in putrescine levels delay seizure onset.
Figure 3: PTZ-induced seizures occur in the optic tectum, but do not alter many of the intrinsic and synaptic properties of tectal neurons.
Figure 4: Priming seizures and direct putrescine administration both increase GABA spontaneous frequency in tectal neurons.
Figure 5: Putrescine converts to GABA in substantial quantities after a seizure.
Figure 6: Disruption of GABABRs by the GABABR antagonist CGPb in conjunction with priming seizures causes decreases in seizure onset latencies.
Figure 7: GABABRs are a likely target of putrescine-converted GABA.
Figure 8: Blocking putrescine production during a seizure results in long-term damage.

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Acknowledgements

We would like to thank B. Connors and J. Kauer with helpful discussion and suggestions to the manuscript. We also thank I. Sears, B. Clarkson and E. Stackpole for technical support and J. Lippman Bell for editorial support. This work was supported by the American Heart Association and the US National Institutes of Health. C.D.A. was also supported by the Klingenstein Fund, M.R.B. by a Graduate Research Fellowship Program award from the National Science Foundation, J.A.B. by a Brain Science Siravo Award for Epilepsy Research and H.F.J. by a Brown University Undergraduate Teaching and Research Award.

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  1. Department of Neuroscience, Brown University, Providence, Rhode Island, USA

    Mark R Bell, James A Belarde, Hannah F Johnson & Carlos D Aizenman

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  1. Mark R Bell
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Contributions

M.R.B. conducted the experiments and wrote the manuscript. J.A.B. contributed to the behavioral testing. H.F.J. contributed to the behavioral testing and the ELISA. C.D.A. supervised the project and edited the manuscript.

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Correspondence to Carlos D Aizenman.

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Xenopus tapole induced PTZ seizures. (MOV 4731 kb)

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Bell, M., Belarde, J., Johnson, H. et al. A neuroprotective role for polyamines in a Xenopus tadpole model of epilepsy. Nat Neurosci 14, 505–512 (2011). https://doi.org/10.1038/nn.2777

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