Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

Abstract

Epilepsy, a disease characterized by abnormal brain activity, is a disabling and potentially life-threatening condition for nearly 1% of the world population. Unfortunately, modulation of brain excitability using available antiepileptic drugs can have serious side effects, especially in the developing brain, and some patients can only be improved by surgical removal of brain regions containing the seizure focus. Here, we show that bilateral transplantation of precursor cells from the embryonic medial ganglionic eminence (MGE) into early postnatal neocortex generates mature GABAergic interneurons in the host brain. In mice receiving MGE cell grafts, GABA-mediated synaptic and extrasynaptic inhibition onto host brain pyramidal neurons is significantly increased. Bilateral MGE cell grafts in epileptic mice lacking a Shaker-like potassium channel (a gene mutated in one form of human epilepsy) resulted in significant reductions in the duration and frequency of spontaneous electrographic seizures. Our findings suggest that MGE-derived interneurons could be used to ameliorate abnormal excitability and possibly act as an effective strategy in the treatment of epilepsy.epilepsy ͉ inhibition ͉ neocortex ͉ therapy ͉ graft

Interneuron Progenitors Attenuate the Power of Acute Focal Ictal Discharges

“…To further investigate the relationship between the number of transplant cells and the attenuation of ictal power propagation, we plotted cell transplant number against the ratio of LFP-2/LFP-1 power, a value that represents efficacy in attenuation of propagation. We presumed that inhibitory neuronal cell density would correlate with efficacy, consistent with the notion that the transplanted cells were making inhibitory synapses on the surrounding pyramidal cells and dampening down the excitatory activity, as has been hypothesized in prior publications [12]. Surprisingly, there was no significant correlation between cell number and the LFP-2/LFP-1 ratio (Fig.…”

“…tissue engineered to release the potent anti-epileptic adenosine [7,8]. However, only recently have advances in understanding cortical interneuron origins [9] and appreciation of their remarkable ability to migrate and survive after transplantation into neonatal or adult cortex [10] ultimately led to interneuron transplantation studies to treat seizures in rodents [11][12][13]. Although species differences with primates appear to exist, in rodents and ferrets most cortical interneurons, including the PV and the SST expressing subgroups, originate in the medial ganglionic eminence (MGE) of the subcortical telencephalon [14].…”

“…In the first study, transplants into neonatal neocortex reduced generalized seizures and modestly improved survival in a genetic model of cortical hyperexcitability [12]. In the second study, reduced seizure threshold produced in adult mice by selective killing of hippocampal interneurons was normalized by transplantation of MGE-derived interneurons [13].…”

Dysfunction of hippocampal interneurons in epilepsy

“…Type I cells have brief-duration action potentials and little or no frequency adaptation of spike discharge to dep olarizing current pulses, whereas type II cells have long-duration action potentials and adaptation of spike discharge to depolarizing current pulses. Later, a "stuttering" pattern in cortex [18] and late-and burst-spiking in the hippocampus [19] (Fig. 1) were included in the primary physiological classes.…”

“…Cell transplantation may repair neuronal circuits in the epileptic brain (Fig. 2B) in epileptic mice lacking the Shaker-like K + channel [18] .…”