Editors' ChoiceEpilepsy

Transplanting Interneuron Precursors for Epilepsy Control

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Science Translational Medicine  24 Jul 2013:
Vol. 5, Issue 195, pp. 195ec122
DOI: 10.1126/scitranslmed.3006984

Certain interneurons in the brain—those that use the neurotransmitter γ-aminobutyric acid (GABA)—inhibit the activity of neuronal circuits and prevent the uncontrolled excitation that characterizes a seizure. Hunt et al. study a mouse model of temporal lobe epilepsy, the most common type of epilepsy in adults, and find that transplantation of precursors for these GABAergic interneurons, even after the onset of seizures, can eliminate or dramatically reduce seizure frequency and ameliorate the ensuing behavioral deficits.

The authors studied mice treated with pilocarpine, which exhibit status epilepticus (a full-body seizure), and then the development of spontaneous seizures and mossy fiber sprouting, a prominent anatomical response also seen in the hippocampi of patients with temporal lobe epilepsy. After the spontaneous seizures had commenced, Hunt et al. injected precursor cells for GABA-releasing (GABAergic) interneurons into either the hippocampus or amygdala of these mice. The precursors were derived from the medial ganglion eminence of control fetal mice at embryonic day 13.5. This brain area is the source of most of the GABAergic interneurons in the hippocampus and neocortex.

Many of the transplanted precursor cells survived, migrated, and developed morphologies, physiological properties, and patterns of gene expression characteristic of the mature interneurons normally born in the medial ganglion eminence. Most important, seizure frequency was reduced by 92% in mice with cells transplanted to the hippocampus, even though anatomic changes, such as mossy fiber sprouting, persisted after transplantation. By contrast, transplantation of the cells into the amygdala failed to reduce seizure frequency. Some of the behavioral deficits in the pilocarpine-treated mice, including impairments in spatial learning, were also rescued by hippocampal transplantation.

Interneuron precursors may represent a powerful cell therapy for epilepsy. A critical next step in translating this work to patients will be the development of human cell lines similar the precursor cells from the medial ganglion eminence. This strategy may also be useful for other conditions associated with deficient GABAergic interneuron function such as schizophrenia and autism.

R. F. Hunt et al., GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat. Neurosci. 16, 692–697 (2013). [Abstract]

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