The promise of an interneuron-based cell therapy for epilepsy

Abstract

Of the nearly 3 million Americans diagnosed with epilepsy, approximately 30% are unresponsive to current medications. Recent data has shown that early postnatal transplantation of interneuronal precursor cells increases GABAergic inhibition in the host brain and dramatically suppresses seizure activity in epileptic mice. In this review, we will highlight findings from seizure-prone mice and humans that demonstrate the link between dysfunctional GABAergic inhibition and hyperexcitability. In particular, we will focus on rodent models of temporal lobe epilepsy, the most common and difficult to treat form of the disease, and interneuronopathies, an emerging classification. A wealth of literature showing a causal link between reduced GABA-mediated inhibition and seizures has directed our efforts to recover the loss of inhibition via transplantation of interneuronal precursors. Numerous related studies have explored the anticonvulsant potential of cell grafts derived from a variety of brain regions, yet the mechanism underlying the effect of such heterogeneous cell transplants is unknown. In discussing our recent findings and placing them in context with what is known about epilepsy, and how related transplant approaches have progressed, we hope to initiate a frank discussion of the best path toward the translation of this approach to patients with intractable forms of epilepsy.

Figure 1

A summary of the neonatal MGE cell transplantation protocol. GFP⁺ MGE cells from E13.5 mice were transplanted into the P2 mouse neocortex. 30–60 days after transplantation (DAT), host mice were used for immunohistochemical, electrophysiological, electron microscopic, electroencephalographic and behavioral analysis. Primary findings are summarized in the text box (right)

Figure 2

Following adult hippocampal transplantation, GFP⁺ graft-derived cells become functional neurons. A. An adult CD-1 mouse (P101) received a GFP⁺ MGE cell graft and was sacrificed 47 DAT for electrophysiological analysis. B. Image of GFP+ cell for which the recordings are shown in C and D. C. Cell fired action potentials with fast afterhyperpolarizations that are characteristic of interneurons. Excitatory postsynaptic potentials (EPSPs) can be seen during and after the hyperpolarizing current step. D. Use of an internal solution containing KGluconate and KCl (Bacci et al., 2003) allowed voltage clamp recordings from the same cell. Spontaneous inhibitory postsynaptic currents (IPSCs) recorded in the presence of glutamate receptor blockers demonstrate that GFP⁺ cells receive inhibitory synaptic input. V_hold = −60 mV.