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

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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Figure 1: Transplanted MGE cells migrate into the adult hippocampus and express markers of inhibitory neurons.
Figure 2: Transplanted MGE cells differentiate into functional inhibitory interneurons.
Figure 3: Distribution of MGE-derived cells 60+ DAT into the adult epileptic hippocampus.
Figure 4: Distribution of MGE-derived cells 60+ DAT into the adult epileptic amygdala.
Figure 5: Inhibitory neuron transplantation reduces seizure occurrence in epileptic mice.
Figure 6: Inhibitory neuron transplantation rescues behavioral comorbidities of epilepsy.

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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.).

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Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Robert F Hunt or Scott C Baraban.

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Competing interests

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

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1–4 (PDF 1659 kb)

Supplementary Movie 1

Example of a spontaneous seizure (MOV 7049 kb)

Supplementary Movie 2

MGE cell transplantation into hippocampus rescues aggressive response to handling (MOV 6013 kb)

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Hunt, R., Girskis, K., Rubenstein, J. et al. GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat Neurosci 16, 692–697 (2013). https://doi.org/10.1038/nn.3392

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