Transplantation of GABAergic Interneurons into the Neonatal Primary Visual Cortex Reduces Absence Seizures in Stargazer Mice

Abstract

Epilepsies are debilitating neurological disorders characterized by repeated episodes of pathological seizure activity. Absence epilepsy (AE) is a poorly understood type of seizure with an estimated 30% of affected patients failing to respond to antiepileptic drugs. Thus, novel therapies are needed for the treatment of AE. A promising cell-based therapeutic strategy is centered on transplantation of embryonic neural stem cells from the medial ganglionic eminence (MGE), which give rise to gamma-aminobutyric acidergic (GABAergic) interneurons during embyronic development. Here, we used the Stargazer (Stg) mouse model of AE to map affected loci using c-Fos immunohistochemistry, which revealed intense seizure-induce activity in visual and somatosensory cortices. We report that transplantation of MGE cells into the primary visual cortex (V1) of Stg mice significantly reduces AE episodes and lowers mortality. Electrophysiological analysis in acute cortical slices of visual cortex demonstrated that Stg V1 neurons exhibit more pronounced increases in activity in response to a potassium-mediated excitability challenge than wildtypes (WT). The defective network activity in V1 was significantly altered following WT MGE transplantation, associating it with behavioral rescue of seizures in Stgs. Taken together, these findings present MGE grafting in the V1 as a possible clinical approach in the treatment of AE.

Synaptic integration of transplanted interneuron progenitor cells into native cortical networks

“…This subtype-specific functional integration, observed to be complete by 35 days after transplantation (DAT), contrasts with an earlier suggestion that MGE-derived interneurons may alter network excitability in a nonspecific fashion at times before these cells become mature, e.g., 7 to 14 DAT (De la Cruz et al 2011;Hammad et al 2015;Southwell et al 2014). Our findings also suggest that emergence of subtype-specific physiological properties is determined early in development and, like interneuron precursor migration and subtype specification (Batista-Brito et al 2009;Wichterle et al 1999;Zhou et al, 2015), is cell autonomous.…”

“…Our findings also suggest that emergence of subtype-specific physiological properties is determined early in development and, like interneuron precursor migration and subtype specification (Batista-Brito et al 2009;Wichterle et al 1999;Zhou et al, 2015), is cell autonomous. Transplanted MGE progenitors have been widely shown to generate neurons expressing markers consistent with an interneuron phenotype, e.g., GAD67, GABA, PV, Sst, and NPY (Alvarez-Dolado et al 2006;Calcagnotto et al 2010;De la Cruz et al 2011;Hammad et al 2015;Henderson et al 2014;Howard et al 2014;Hunt et al 2014;Southwell et al 2010;Wichterle et al 1999). Using electrophysiological recording techniques, we now show that expression of these interneuron subtype-specific markers, PV in particular, is coincident with the functional development of a specific set of synaptic and intrinsic physiological properties.…”

“…Consistent with these findings, a near complete suppression of spontaneous seizures is observed with MGE progenitor cell transplantation as early as 30 DAT in genetic or acquired mouse models of chronic epilepsy (Baraban et al 2009;Henderson et al 2014;Hunt et al 2013). However, suppression of acutely evoked or absence-like seizure events was also reported as early as 7 to 17 DAT (De la Cruz et al 2011;Hammad et al 2015), e.g., a time when only immature MGE-derived interneurons with migratory morphology are present (Alvarez-Dolado et al 2006).…”

Developmentally defined forebrain circuits regulate appetitive and aversive olfactory learning

“…No data points were removed from statistical analyses. Sample sizes for behavioral experiments were not determined statistically but are in accordance with common practice 1, 2 . All statistical analyses were conducted in Microsoft Excel and GraphPad Prism.…”

Transplantation of GABAergic interneurons for cell-based therapy

“…A 90% reduction in seizure events was observed in grafted mutant animals over the course of a month-long monitoring period. In another model of acquired epilepsy (Hammad et al, 2015), neonatal transplantation of MGE cells also yielded a significant decrease in the frequency and duration of epilepsy episodes, as early as 3 weeks posttransplantation. Concomitantly, transplantation seemed to promote survival of the mutant animals, as 80% of the MGE graft recipients survived up to 4 months compared to an average survival of 29 days for control animals.…”