Transplantation of neural progenitor cells raises great expectations for the treatment of neurological disorders. A number of recent studies, including those from our laboratory (Wichertle et al. 1999;Alvarez-Dolado et al. 2006), demonstrate that transplanted progenitor cells derived from the embryonic medial ganglionic eminence (MGE) possess a unique ability to disperse, migrate, and differentiate into GABAergic interneurons. Although we recently demonstrated that these cells are effective in suppressing spontaneous seizures in a mutant mouse model of epilepsy (Baraban et al. 2009), the therapeutic potential of this approach remains largely unexplored. In response to recent NINDS epilepsy research """"""""benchmarks"""""""", we here propose experiments to develop an adult transplantation strategy using MGE progenitors harvested from mouse embryos or derived from mouse embryonic stem cells. These cells will be transplanted in a common rodent model of temporal lobe epilepsy after the emergence of spontaneous seizures. Techniques will involve use of acute brain slices maintained in vitro, and application of visualized patch clamp methods to study the functional integration of MGE-derived interneurons. Video-EEG monitoring and immunofluorescence techniques will also be applied.
Three specific aims are proposed: (i) to develop, optimize, and validate a method for transplantation of MGE progenitor cells in the adult mouse hippocampus (ii) to examine the therapeutic potential of adult MGE progenitor cell grafts in a mouse model of temporal lobe epilepsy, and (iii) to develop an MGE progenitor cell line from mouse embryonic stem cells. Our results promise to provide new information about the function of transplanted MGE progenitors in the adult host brain and may provide a direct demonstration of the potential for progenitor cells to treat epilepsy.
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 and stem cell derived neural progenitor cells and a common rodent model of temporal lobe epilepsy we propose to develop a novel interneuron-based cell therapy.
|Hunt, Robert F; Baraban, Scott C (2015) Interneuron Transplantation as a Treatment for Epilepsy. Cold Spring Harb Perspect Med 5:|
|Howard, MacKenzie Allen; Rubenstein, John L R; Baraban, Scott C (2014) Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo. Proc Natl Acad Sci U S A 111:492-7|
|Stanco, Amelia; Pla, Ramón; Vogt, Daniel et al. (2014) NPAS1 represses the generation of specific subtypes of cortical interneurons. Neuron 84:940-53|
|Vogt, Daniel; Hunt, Robert F; Mandal, Shyamali et al. (2014) Lhx6 directly regulates Arx and CXCR7 to determine cortical interneuron fate and laminar position. Neuron 82:350-64|
|Sebe, Joy Y; Looke-Stewart, Elizabeth; Baraban, Scott C (2014) GABAB receptors in maintenance of neocortical circuit function. Exp Neurol 261:163-70|
|Sebe, Joy Y; Looke-Stewart, Elizabeth; Dinday, Matthew T et al. (2014) Neocortical integration of transplanted GABA progenitor cells from wild type and GABA(B) receptor knockout mouse donors. Neurosci Lett 561:52-7|
|Hunt, Robert F; Girskis, Kelly M; Rubenstein, John L et al. (2013) GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat Neurosci 16:692-7|
|Chen, Ying-Jiun J; Vogt, Daniel; Wang, Yanling et al. (2013) Use of ""MGE enhancers"" for labeling and selection of embryonic stem cell-derived medial ganglionic eminence (MGE) progenitors and neurons. PLoS One 8:e61956|
|Southwell, Derek G; Paredes, Mercedes F; Galvao, Rui P et al. (2012) Intrinsically determined cell death of developing cortical interneurons. Nature 491:109-13|