Transplant of GABAergic Precursors Restores Hippocampal Inhibitory Function in a Mouse Model of Seizure Susceptibility

Abstract

Defects in GABAergic function can cause epilepsy. In the last years, cell-based therapies have attempted to correct these defects with disparate success on animal models of epilepsy. Recently, we demonstrated that medial ganglionic eminence (MGE)-derived cells grafted into the neonatal normal brain migrate and differentiate into functional mature GABAergic interneurons. These cells are able to modulate the local level of GABA-mediated synaptic inhibition, which suggests their suitability for cell-based therapies. However, it is unclear whether they can integrate in the host circuitry and rescue the loss of inhibition in pathological conditions. Thus, as proof of principle, we grafted MGE-derived cells into a mouse model of seizure susceptibility caused by specific elimination of GABAergic interneuron subpopulations in the mouse hippocampus after injection of the neurotoxic saporin conjugated to substance P (SSP-Sap). This ablation was associated with significant decrease in inhibitory postsynaptic currents (IPSC) on CA1 pyramidal cells and increased seizure susceptibility induced by pentylenetetrazol (PTZ). Grafting of GFP(+) MGE-derived cells in SSP-Sap-treated mice repopulates the hippocampal ablated zone with cells expressing molecular markers of mature interneurons. Interestingly, IPSC kinetics on CA1 pyramidal cells of ablated hippocampus significantly increased after transplantation, reaching levels similar to the normal mice. More importantly, this was associated with reduction in seizure severity and decrease in postseizure mortality induced by PTZ. Our data show that MGE-derived cells fulfill most of the requirements for an appropriate cell-based therapy, and indicate their suitability for neurological conditions where a modulation of synaptic inhibition is needed, such as epilepsy.

Interneuron Progenitors Attenuate the Power of Acute Focal Ictal Discharges

“…Another promising approach involved the transplantation of embryonic stem cells engineered to produce adenosine [7,8]. The current study takes an alternate approach from these studies in that the cells used for transplantation derive from the embryonic source of most [12,13,18]. In this report, we confirm the therapeutic efficacy of these transplants and extend the indications to adult rodent neocortex.…”

“…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]. Finally, MGEderived neural stem cells transplanted into adult hippocampus reduced kainic acid-induced kindled seizures, although in this study the grafts included many astrocytes [11].…”

“…Baraban et al [12] then showed that grafted MGE cells exhibit anti-epileptic effects in a Kv1.1 mutant mouse model of generalized epilepsy and demonstrated synaptogenesis at posttransplantation day 30 by electron microscopy, in addition to increases in inhibitory tone. Zipancic et al [13] demonstrated reduced seizure threshold after transplantation of MGE cells into the adult hippocampus of a rodent model receiving a neurotoxin against GABAergic subpopulations in the hippocampus. However, only 20% of the grafted cells survived.…”

“…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].…”

Dysfunction of hippocampal interneurons in epilepsy

“…However, fetal CA1 cell grafts do not induce interneurons that increa se inhibition in the host [19,91,92] .…”