Transplantation of GABA progenitors into the central nervous system has shown great promise for the treatment of neurological disease. Our laboratories demonstrated that GABA-expressing interneurons, derived from the rodent embryonic medial ganglionic eminence (MGE), migrate, integrate, and increase inhibition following transplantation. Potential therapeutic benefits of these cells were reported in animal models of: epilepsy, Parkinson's disease, Alzheimer's disease, neuropathic pain, schizophrenia, anxiety and psychosis. During the previous NIH-supported funding cycle and in response to NINDS epilepsy research benchmarks, we developed an adult transplantation strategy using MGE progenitors harvested from mouse embryos, and published the first studies demonstrating that MGE transplantation dramatically suppressed spontaneous seizures and improved cognitive or behavioral co-morbidities in an animal model of acquired epilepsy. These findings are consistent with our hypothesis that enhancement of GABA-mediated inhibition - through the generation of new interneurons - provides therapeutic benefit in conditions featuring excess excitation such as epilepsy. Translation of these findings to the clinic, ultimately, requires a more complete understanding of underlying mechanism(s). However, studies of MGE transplantation have not adequately addressed the question of how distinct interneuron sub-population(s) influence host circuitry and which sub-types are necessary for the therapeutic activity observed. To address these issues, we propose experiments to study progenitors harvested from the medial and caudal ganglionic eminences. These cells will be transplanted in neonatal and adult hippocampus, and in a common rodent model of acquired epilepsy. Donor mice will incorporate interneuron-specific Cre-recombinase lines, as well as floxed, channelrhodopsin (CHR2), vesicular GABA transporter deficient (VGAT), and diphtheria toxin (DT) animals. Techniques will involve use of acute brain slices maintained in vitro, visualized patch clamp recording in combination with optogenetic stimulation, and viral synaptic tracers. Video-EEG monitoring, immunofluorescence, behavior and confocal microscopy techniques will also be applied.
Two specific aims are proposed: (i) to evaluate integration of transplanted progenitor cells in the host brain, and (ii) to identify interneuron sub-population(s) necessary fo the therapeutic benefits of transplanted progenitor cells. Our results promise to advance our long-term goal to develop a novel interneuron-based cell therapy for intractable epilepsies.
Epilepsy is a common neurological disorder afflicting nearly 3 million Americans. Given that loss or reduction of inhibitory synaptic transmission in hippocampus is one potential mechanism resulting in the emergence of epilepsy, a method to generate new hippocampal interneurons could have direct therapeutic consequences. Using mouse embryonic neural progenitor cells and a rodent model of epilepsy we propose to better understand and develop a novel interneuron-based cell therapy.
