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GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior

Nature Neuroscience volume 16, pages 692697 (2013) | Download Citation

Abstract

Impaired GABA-mediated neurotransmission has been implicated in many neurologic diseases, including epilepsy, intellectual disability and psychiatric disorders. We found that inhibitory neuron transplantation into the hippocampus of adult mice with confirmed epilepsy at the time of grafting markedly reduced the occurrence of electrographic seizures and restored behavioral deficits in spatial learning, hyperactivity and the aggressive response to handling. In the recipient brain, GABA progenitors migrated up to 1,500 μm from the injection site, expressed genes and proteins characteristic for interneurons, differentiated into functional inhibitory neurons and received excitatory synaptic input. In contrast with hippocampus, cell grafts into basolateral amygdala rescued the hyperactivity deficit, but did not alter seizure activity or other abnormal behaviors. Our results highlight a critical role for interneurons in epilepsy and suggest that interneuron cell transplantation is a powerful approach to halting seizures and rescuing accompanying deficits in severely epileptic mice.

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Acknowledgements

We thank M. Dinday and W. Hindle-Katel for assistance with pilocarpine injections, J. Sebe for tissue dissection training, G. Hortopan for advice on the single-cell RT-PCR procedure, R. Palmiter for the ZnT3 antibody, and S. Canchola for training on behavior assays. This work was supported by funding from US National Institutes of Health grants from the National Institute of Neurological Disorders and Stroke (RO1-NS071785 to S.C.B., J.L.R. and A.A.-B., and F32-NS077747 to R.F.H.), and a grant from the California Institute of Regenerative Medicine (#TR2-01749 to A.A.-B. and S.C.B.).

Author information

Affiliations

  1. Epilepsy Research Laboratory, University of California, San Francisco, California, USA.

    • Robert F Hunt
    • , Kelly M Girskis
    •  & Scott C Baraban
  2. Department of Neurological Surgery, University of California, San Francisco, California, USA.

    • Robert F Hunt
    • , Kelly M Girskis
    • , Arturo Alvarez-Buylla
    •  & Scott C Baraban
  3. Department of Psychiatry, University of California, San Francisco, California, USA.

    • John L Rubenstein

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Contributions

R.F.H. contributed to the concept, design, execution and analysis of all of the experiments, provided funding, and wrote the manuscript. K.M.G. contributed to the execution and analysis of the immunostaining and behavior experiments. J.L.R. and A.A.-B. contributed to the concept, provided funding and edited the manuscript. S.C.B. contributed to the concept and design of the experiments, analyzed the EEG data, provided funding, and wrote the manuscript.

Competing interests

S.C.B., J.L.R. and A.A.-B. are cofounders of and have a financial interest in Neurona Therapeutics.

Corresponding authors

Correspondence to Robert F Hunt or Scott C Baraban.

Supplementary information

PDF files

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    Supplementary Text and Figures

    Supplementary Figures 1–6 and Supplementary Tables 1–4

Videos

  1. 1.

    Supplementary Movie 1

    Example of a spontaneous seizure

  2. 2.

    Supplementary Movie 2

    MGE cell transplantation into hippocampus rescues aggressive response to handling

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DOI

https://doi.org/10.1038/nn.3392

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