Interneuron Transplantation as a Treatment for Epilepsy

Abstract

Stem-cell therapy has extraordinary potential to address critical, unmet needs in the treatment of human disease. One particularly promising approach for the treatment of epilepsy is to increase inhibition in areas of the epileptic brain by grafting new inhibitory cortical interneurons. When grafted from embryos, young g-aminobutyric acid (GABA)ergic precursors disperse, functionally mature into host brain circuits as local-circuit interneurons, and can stop seizures in both genetic and acquired forms of the disease. These features make interneuron cell transplantation an attractive new approach for the treatment of intractable epilepsies, as well as other brain disorders that involve increased risk for epilepsy as a comorbidity. Here, we review recent efforts to isolate and transplant cortical interneuron precursors derived from embryonic mouse and human cell sources. We also discuss some of the important challenges that must be addressed before stem-cell-based treatment for human epilepsy is realized.

Medial Ganglionic Eminence Progenitors Transplanted into Hippocampus Integrate in a Functional and Subtype-Appropriate Manner

“…1 D ). These results using ChR2 mouse donor embryos are consistent with previous studies (Alvarez-Dolado et al, 2006; Baraban et al, 2009; Southwell et al, 2012; Hunt et al, 2013; Howard et al, 2014; Sebe et al, 2014a, 2014b; Hunt and Baraban, 2015; Howard and Baraban, 2016)…”

Persistent seizure control in epileptic mice transplanted with gamma‐aminobutyric acid progenitors

“…CGE progenitors transplanted into adult mouse hippocampus also migrate and integrate as GABAergic neurons 12,13 . In contrast to MGE, CGE transplanted progenitors primarily differentiate to calretinin, vasoactive intestinal protein (VIP) and reelin-positive interneuron sub-populations shown to form functional synapses with excitatory and inhibitory neurons.…”

“…Because interneurons derived from the CGE can migrate and integrate when transplanted in the neonatal or adult brain 12,13,48 , we also tested whether CGE progenitors could be beneficial for epilepsy therapy. As small numbers of migrating MGE progenitors can contaminate anatomical CGE transplants 48 we used a genetic manipulation to ablate Nkx2.1 + MGE progenitor cells from our CGE transplants 13 .…”

Transplantation of GABAergic interneurons for cell-based therapy

“…As the CGE is a caudal extension of both LGE and MGE, using the most rostral aspect of the CGE for transplantation may give rise to grafts enriched in LGE-derived cells that exhibit poor dispersal (Wichterle et al, 1999). However, in line with genetic fate mapping studies (Miyoshi et al, 2010; Rudy et al, 2011), CGE transplant-derived interneurons were more likely to localize to cortical layer I (Larimer et al, 2016) and express VIP, CR, and RLN (Hunt and Baraban, 2015; Isstas et al, 2016; Larimer et al, 2016) (Fig. 2).…”

“…1). Not surprisingly, CGE transplant-derived cells were found to migrate extensively following heterochronic transplantation in the neonatal brain, with a dispersal similar to that of MGE cells (Hunt and Baraban, 2015; Larimer et al, 2016), thus suggesting that tangential migration of ventral forebrain inter-neuron precursors is a determinant factor for their dispersal upon transplantation. However, conflicting results were found following transplantation in the adult brain, with one report describing the failure of CGE cells to disperse in the mature cortex (Davis et al, 2015) and another study showing accentuated dispersal of CGE cells compared to that of MGE cells (Isstas et al, 2016).…”