Hippocampal transplants of fetal GABAergic progenitors regulate adult neurogenesis in mice with temporal lobe epilepsy

Abstract

GABAergic interneurons play a role in regulating adult neurogenesis within the dentate gyrus (DG) of the hippocampus. Neurogenesis occurs within a stem cell niche in the subgranular zone (SGZ) of the DG. In this niche, populations of neural progenitors give rise to granule cells that migrate radially into the granule cell layer (GCL) of the DG. Altered neurogenesis in temporal lobe epilepsy (TLE) is linked to a transient increase in the proliferation of new neurons and the abnormal inversion of Type 1 progenitors, resulting in ectopic migration of Type 3 progenitors into the hilus of the DG. These ectopic cells mature into granule cells in the hilus that become hyperexcitable and contribute to the development of spontaneous recurrent seizures. To test whether grafts of GABAergic cells in the DG restore synaptic inhibition, prior work focused on transplanting GABAergic progenitors into the hilus of the DG. This cell-based therapeutic approach was shown to alter the disease phenotype by ameliorating spontaneous seizures in mice with pilocarpine-induced TLE. Prior optogenetic and immunohistochemical studies demonstrated that the transplanted GABAergic interneurons increased levels of synaptic inhibition by establishing inhibitory synaptic contacts with adult-born granule cells, consistent with the observed suppression of seizures. Whether GABAergic progenitor transplantation into the DG ameliorates underlying abnormalities in adult neurogenesis caused by TLE is not known. As a first step to address this question, we compared the effects of GABAergic progenitor transplantation on Type 1, Type 2, and Type 3 progenitors in the stem cell niche using cell type-specific molecular markers in naïve, non-epileptic mice. The progenitor transplantation increased GABAergic interneurons in the DG and led to a significant reduction in Type 2 progenitors and a concomitant increase in Type 3 progenitors. Next, we compared the effects of GABAergic interneuron transplantation in epileptic mice. Transplantation of GABAergic progenitors resulted in reductions in inverted Type 1, Type 2, and hilar ectopic Type 3 cells, concomitant with an increase in the radial migration of Type 3 progenitors into the GCL. Thus, in mice with Pilocarpine induced TLE, hilar transplants of GABA interneurons may reverse abnormal patterns of adult neurogenesis, an outcome that may ameliorate seizures.