Temporal lobe epilepsy (TLE) is a prevalent and debilitating neurological disorder that exhibits high rates of pharmacological resistance to treatment. For these patients, neuro-stimulation or surgical intervention is often necessary. However, less invasive novel TLE therapies are needed, particularly cell-based treatments which offer the potential to rescue underlying neural circuit abnormalities. Hippocampal grafts of GABAergic interneuron progenitors, harvested from the embryonic medial ganglionic eminence (MGE) or human pluripotent stem cells, are efficacious for seizure suppression, neural circuit repair, and cognitive remediation in TLE rodent models. However, the specific neurobiological mechanisms underlying these therapeutic effects are not well understood. Prior studies established that the transplanted cells form synaptic connections with host brain hippocampal neurons and induce postsynaptic inhibitory currents, suggesting that synaptic inhibition is responsible for seizure suppression following interneuron transplantation. To further test whether synaptic inhibition is required for the therapeutic effects of MGE transplants on seizure incidence and severity, we utilized a combination of genetic, electrophysiological, and immunohistochemical methods in mice with acquired TLE to investigate whether vesicular GABA release from the transplanted cells is required for seizure suppression. Specifically, we tested the effects of transplanting MGE-derived progenitor cells that were deficient in VGAT (VGAT+/- and VGAT-/-) through Cre/Lox-mediated excision. Transplants were engrafted in dorsal and ventral locations of the dentate gyrus in TLE mice that acquired recurrent seizures following chemically induced status epilepticus. The incidence and behavioral severity of seizures were assessed over two to three weeks of continuous video-electroencephalography (V-EEG) recordings. Comparisons between TLE mice that received VGAT-deficient or wildtype MGE cell grafts and media injections suggest that transplant-mediated vesicular GABA release is a critical mechanism, but not the only mechanism, underlying in vivo seizure suppression. Specifically, vesicular GABA release appears to most directly attenuate the behavioral severity of manifested seizures, but not necessarily the total number or frequency of seizures within a cluster. Finally, the present study is a novel proof-of-concept for using VGAT-deficient progenitor cells in preclinical TLE transplantation studies: allowing for the mechanistic determination of which therapeutic effects require synaptic inhibition.
"},{"label":"Degree","value":["Bachelor of Arts with Departmental Honors"]},{"label":"Author-supplied Keywords","value":["Tle","Interneuron","GABA"]},{"label":"Administrative Note","value":"Drupal Node ID: 28347