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Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

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Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.

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Cell Therapy Using GABAergic Neural Progenitors

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Cell transplantation may repair neural circuits in the epileptic brain. Grafted cells should disperse, migrate and functionally integrate. Generation of inhibitory interneurons with these abilities could be therapeutic in a condition of abnormal neuronal hyperexcitability i.e., epilepsy. This review will discuss recent efforts to isolate and transplant interneuron precursor cells derived from the medial ganglionic eminence.

It is proposed, first, to give a general account of the origin of inhibitory interneurons with special reference to the medial ganglionic eminence (MGE). It will be recognized that young neurons born in the MGE can migrate a long distance and give rise to several interneuron sub-types following transplantation into the postnatal brain. Following this initial treatment, there will be an account of the functional integration of transplanted MGE cells more relevant to the treatment of epilepsy, namely the ability to integrate as mature interneurons, increase GABA-mediated inhibition in host circuits and ameliorate epileptic phenotypes. Finally, we will then give an account of novel approaches to generate MGE-like cell lines from embryonic stem cells.

EMBRYONIC ORIGIN OF CORTICAL INTERNEURONS

Pioneering work in the late 1990’s confirmed the concept that neurons arising in the ganglionic eminences of the ventral subpallium of the telencephalon migrate in a tangential manner to developing neocortex, hippocampus and olfactory bulb where they generate GABA-containing interneurons.1–3 These cells are thought to arise from two primary, and transient, embryonic structures known as the medial and caudal ganglionic eminences (MGE and CGE, respectively).4,5 Seminal studies of interneuron migration in explants6,7 and in vivo fate-mapping8,9 revealed distinct sub-types of cortical interneurons that arise from each of these two locations. The MGE mainly gives rise to two neurochemically-defined subgroups, those that express the calcium binding protein parvalbumin (PV), and those that express the neuropeptide somastostatin10,11; the CGE gives rise to vertically oriented, calretinin and VIP expressing interneurons10,11, as well as NPY and reelin expressing neurogliaform subclasses.12,13 Within these neurochemically-defined subgroups there are numerous interneuron subtypes defined by combinations of neurochemical, physiological, and axon-targeting criteria.14

Genetically engineered mice lacking transcription factors expressed in these embryonic regions (e.g., Dlx1 or Mash1) lack interneurons confirming a ventral telencephalic origin for these cells and, relevant to this volume, demonstrate that the consequence of interneuron deficiency is often epilepsy. For example, inactivation of a homeobox transcription factor, Dlx1, resulted in mutant mice featuring an age-dependent loss of somatostatin+, NPY+, and calretinin+ interneurons (identified through immunohistochemical and in situ hybridization studies) with a subsequent reduction in cortical/hippocampal inhibition (evaluated in acute slice experiments) and spontaneous electrographic seizures (assessed in video-EEG recordings).15 Late-onset epilepsy in these Dlx1 mutants, and another mouse with subtype-specific reductions in cortical interneuron density i.e., uPAR−/− mice16 provide strong support for the hypothesis that correct interneuron number and function plays a key antiepileptic role in the adult CNS. Decreased numbers of PV+ and NPY+ interneurons also correlate with increased seizure susceptibility in a recently described neuropilin-2 knockout mouse17 and genetic manipulation of the aristaless-related homeobox gene (ARX) in mice results in a reduction of cortical calbindin-positive interneurons and a variety of seizure phenotypes.18,19 Taken together, these discoveries and the identification of an epileptic phenotype in children with ARX mutations (and reduced cortical interneuron function) have prompted a new ‘interneuronopathy’ epilepsy designation.20

TRANSPLANTATION OF MGE PRECURSOR CELLS

Grafted neural progenitors can produce functionally integrated neurons, even after host neurogenesis is complete, and in brain areas outside traditional “neurogenic” regions. For example, progenitors derived from fetal midbrain integrate into host striatum as dopaminergic neurons and immortalized neural progenitors (RN33B) transplanted into cortex or hippocampus of neonatal rats differentiate into cells with the morphological features of pyramidal neurons.21 In electrophysiological studies, these cells can generate action potentials and receive excitatory or inhibitory input from neighboring cells. Using grafted embryonic stem (ES) cells expressing green fluorescent protein (GFP) and voltage-clamp analysis of postsynaptic currents, Wernig et al.22 confirmed synapse formation between host and donor neurons. These studies, though elegant in design and buttressed by anatomical data indicating synapse formation onto GFP cells, failed to examine synaptic integration in the opposite direction e.g., donor neuron-to-host brain. Additionally, large tumors were noted in most animals receiving ES-GFP cell grafts. ES-derived neural progenitor cells transplanted into hippocampus also display a “marked tendency” to form tumors23 or appear as “clumps” or “clusters” of cells with mixed lineage near the transplant site.24,25 Although a promising alternative to currently available drug therapies, functional integration of these ES-derived cells within the host brain is probably quite limited.

Immature neurons arising from the embryonic MGE, in stark contrast to ES-derived cell lines, exhibit a unique ability to migrate widely in host brain following early postnatal transplantation.7 MGE-derived cells express neuronal markers such as NeuN and Hu24 but exhibit only limited, or no, expression of non-neuronal markers such as glial fibrillary acidic protein, vimentin, or Olig-2.7,26–29 Transplanted MGE cells are also immune-negative for tyrosine hydroxylase, choline acetyl transferase, CaM kinase IIα or the neuronal glutamate transporter excitatory amino acid carrier-1. Consistent with lineage tracing and fate-mapping studies, nearly all MGE-derived neurons in the host brain are GABAergic and stain with antibodies to GABA or GAD67. Sub-populations of MGE-derived interneurons can be double-labeled with antibodies to parvalbumin, somatostatin, neuropeptide Y and calretinin. Most importantly, MGE-derived neurons can migrate up to 5 mm from the injection site and show signs of synapse formation in electron micrographic studies.7,29,30 These anatomical findings suggest that MGE-derived cells could be a source of new, and functionally integrated, interneurons in the host brain. In vitro electrophysiology studies using GFP-labeled MGE-derived interneurons confirmed that these cells exhibit intrinsic membrane and active firing properties that would classify them as mature interneurons following transplantation.26,27,30 Moreover, as direct evidence that these cells can functionally integrate and influence GABA-mediated inhibition in the host brain, slice electrophysiology studies consistently show an increase in synaptic26,28,30 and extrasynaptic inhibition30 in regions of the host brain containing MGE-derived GFP+ interneurons.

CELL THERAPY USING TRANSPLANTED MGE PRECURSOR CELLS

Epilepsy can be a devastating neurological condition characterized by unpredictable abnormal electrical discharge (seizure) that can result in various combinations of uncontrolled motor output, loss of consciousness and sometimes death. Nearly 3 million Americans suffer with some form of epilepsy, it has long been recognized that loss (or reduction) in GABA-mediated inhibition can be a contributing factor, and available antiepileptic drugs (including those that target GABAergic signaling pathways), are not effective in approximately one-third of these patients. Cell therapy could offer an alternative treatment option. One critical advantage of a transplantation strategy over conventional antiepileptic drug therapy is that cell treatments can be locally restricted, whereas drugs have widespread and systemic adverse effects. What will be critical to the success of this therapy is the type of neuron that is generated. Early attempts at establishing a cell-based therapy for epilepsy used fetal noradrenergic neurons that were grafted bilaterally to the hippocampus of adult rats following a chemical lesion of the central catecholamine pathway.31,32 However, adrenergic cell grafts did not suppress kindling-induced seizure discharge in non-lesioned animals nor did they suppress seizures when grafted post-kindling. Fetal catecholamine-releasing cell grafts were shown to be only moderately effective at suppressing seizure-like activity in a variety of animal models.33,34 Grafting fetal serotonergic or cholinergic neurons was shown to suppress seizures in epilepsy-prone animals where these signaling pathways were lesioned.35,36 Because inhibition is a key deficit in epilepsy, several early attempts to enhance GABA-mediated inhibition have been tried: (i) grafting fetal “GABAergic” neurons putatively derived from the rat embryonic ganglionic eminence (no immunohistochemical confirmation of cell type was performed) only produced modest effects that were similar to those observed with control cell grafts from the sciatic nerve,37 (ii) grafts of fetal GABA-rich cells into substantia nigra produced transient effects on afterdischarge activity in kindled rats,38,39 and (iii) grafting of an immortalized cortical cell line engineered to produce GABA also produced only a modest suppression of afterdischarge activity.39,40 Though encouraging, none of these studies demonstrated a capability to selectively generate interneurons that migrate, function and integrate in host brain in a manner similar to the endogenous interneuron cell population.

Although interneuron dysfunction can be a feature of the epileptic brain and GABA-enhancing or GABA-mimetic antiepileptic drugs are already in widespread clinical use, a strategy to modify host brain circuitry by exploiting the embryonic source of these cells (i.e., MGE) has only recently been explored. Using rat embryonic day 14 fetal tissue to generate putative “MGE” - neural stem cells (NSCs) for in vivo grafting into the hippocampus of rats made chronically epileptic by the intraperitoneal injection of kainic acid, Shetty and coworkers reported a reduction in behaviorally monitored seizure frequency and duration.41 Although it was suggested that increased numbers of new GABAergic interneurons were responsible for the observed suppression of seizure behavior only 10% of graft-derived cells were immunoreactive for GABA in these studies and whether sub-dissection of embryonic MGE was performed prior to derivation of NSC neurospheres was not explicitly described. A more promising result from Zipancic, Calcagnotto and coworkers28 described transplantation of E12.5 embryonic MGE progenitor cells into the hippocampus of adult mice one week after ablation of a subpopulation of GABAergic interneurons using a neurotoxic saporin conjugated to substance P (SSP-Sap). GABA-mediated inhibition, shown to be decreased in voltage-clamp recordings of miniature and spontaneous inhibitory postsynaptic currents from hippocampal slices prepared from SSP-Sap mice, was restored to “normal” levels following MGE transplantation. In additional studies, MGE grafted SSP-Sap mice were found to be less sensitive to pentylenetetrazole (PTZ)-induced seizures than age-matched SSP-Sap control mice. We also used mouse embryonic MGE progenitor cell transplantations in our attempts to develop an interneuron-based cell therapy for epilepsy. First we examined thresholds for induction of seizure activity in wild-type CD1 mice. To induce seizures, we chose the “pilocarpine” model as activity is triggered by cholinergic mechanisms and is sensitive to endogenous GABA tone.42 Acute pilocarpine administration induces ictal and interictal discharge activity in electrographic recordings (Figure 1a), which are correlated with a sequence of behavioral alterations that include akinesia, ataxic lurching, and facial automatisms (Stage II), progressing to tonic-clonic motor seizures (Stage III). Following brief concentration-response studies, a pilocarpine concentration (300 mg/kg, i.p.) was chosen that elicits Stage III seizures in approximately 70% of control mice. As an initial demonstration of “seizure protection” conferred by MGE cell grafts, only 55% of grafted mice were observed to exhibit pilocarpine-induced Stage III seizures at 45 DAT; in all grafted animals post hoc immunohistochemistry was used to confirm the presence of at least 40,000 MGE-GFP cells in cortex. To place MGE graft “protection” data in a therapeutic context, we also pre-administered three conventional antiepileptic drugs (AEDs) and measured pilocarpine-induced Stage III seizure incidence. Interestingly, MGE grafts confer protection that was comparable to available AEDs and clearly superior to at least one, phenytoin (Figure 1b). Next we tested our early MGE transplantation strategy in Kv.1.1 null mice that mimic a human form of epilepsy associated with mutation of the Kv1.1/Kcna1 channel. These mice exhibit a spontaneous seizure frequency of at least one tonic-clonic seizure per hour and were shown to be pre-disposed to sudden unexplained death in epilepsy (SUDEP).43–45 MGE grafts dramatically reduced the frequency of electrographic seizures (Figure 1c) in Kv1.1-deficient mice and when rare electrographic seizure events did occur in grafted animals they were reduced in duration by over 50%.30

Figure 1. MGE cell therapy for epilepsy.

Figure 1

MGE cell therapy for epilepsy. (a) Sample EEG traces from a wild-type CD1 (top), CD1 mouse injected with 300 mg/kg pilocarpine (middle) and Kv1.1−/− mouse (bottom); seizures are observed as high frequency, large amplitude events with durations (more...)

POTENTIAL SOURCES OF MGE-LIKE INTERNEURON PRECURSORS

The publications detailed above provide exciting evidence that interneuron transplantation could become a new therapy for medication-resistant seizures. However, this point begs the obvious question, where would “MGE cells” for such therapy come from? Recently, mouse and human embryonic stem cells (ESCs) have been differentiated into ventral telencephalic progenitors that give rise to GABA+ cells.46–48 One approach is to initially use signaling pathway inhibitors to allow ES cells to take what appears to be, at least for human cells, their default fate of telencephalic, multipotent progenitors.47,49,50 The progenitors are then ventralized to subcortical fates with the morphogen Sonic Hedgehog.48,51 Induced pluripotent stem cells (iPSCs), that are generated by the dedifferentiation of somatic, mitotic cells such as fibroblasts, also default to a telencephalic-like progenitor stage52 and thus should also be amenable to ventralization into MGE-like progenitors of GABA-producing neurons. Conceivably, the latter approach would permit the generation of interneurons from a patient’s own somatic cells.

CONCLUSION

While the above studies demonstrate the feasibility of generating progenitors of GABA+, telencephalic neurons from mouse and human stem cells, none of these determined whether putative MGE-derived cortical interneurons were being generated. This issue is critical since the vast majority of subcortical telencephalic neurons are GABAergic, including several large classes of projection neurons. To achieve this goal, promoter elements from the Lhx6 gene have been used to generate a mouse embryonic stem cell line that, following differentiation to ventral telencephalic progenitors, expresses GFP in putative postmitotic cortical interneuron precursors.53 GFP+ cells from this line migrate extensively after transplantation into neocortex, express markers such as parvalbumin or somatostatin that define cortical interneuron subgroups, and express intrinsic firing properties typical of these subgroups e.g., critical features of MGE-derived progenitors harvested from the mouse embryo. Promoter elements that impart MGE expression of Lhx6 downstream of the interneuron fate determining gene Nkx2.1 are highly conserved between mice and humans, raising the likelihood that the same or similar reporter constructs could also be used to isolate cortical interneuron precursors from telencephalon-directed cultures of human ESCs or IPSCs. However, even if this particular approach is successful at generating putative human interneurons, a major challenge will be proving this point, since either very long-term cultures or xenographic transplants with long-term survival will be needed due to the extended period of maturation of cortical interneurons in humans. Of course, it will then be necessary to demonstrate that these integrated cell lines are capable of suppressing spontaneous seizure activity. These caveats aside, the prospect of developing a new cell-based therapy based on transplantation of GABA progenitor cells is an exciting one and clearly merits further study.

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Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

All Jasper's Basic Mechanisms of the Epilepsies content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported license, which permits copying, distribution and transmission of the work, provided the original work is properly cited, not used for commercial purposes, nor is altered or transformed.

Bookshelf ID: NBK98214PMID: 22787598

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