Multi-potent progenitor cells raise great expectations for the treatment of neurological disorders and have generated considerable interest in the general field of medicine. A number of recent studies, including those from our laboratory (Wichertle et al. 1999), suggest that transplanted progenitors migrate considerable distances and differentiate into morphologically mature neurons in the host central nervous system. For example, progenitor cells derived from medial ganglionic eminence (MGE) have a unique ability to disperse, migrate, and differentiate into GABAergic interneurons in multiple adult brain regions. Although anatomical studies on transplanted progenitors suggest a mature neuronal morphology, the function of these neurons in a host brain remains unknown. In response to a recent NIH program announcement, in this proposal we will asses the ability of transplanted MGE progenitor cells to integrate in the host nervous system and modify a dysfunctional state e.g., epilepsy. Techniques will involve use of acute brain slices maintained in vitro, and application of visualized patch clamp methods to study the physiological function of fluorescently-tagged transplanted MGE cells. Immunohistochemical and electron microscopy experiments will be performed to assess the phenotype of transplanted cells. Mutant mice exhibiting loss of cortical interneurons (uPARv-/-; Dlx-/-) or alterations in synaptic inhibition (GAD657-/-) will be used to evaluate whether transplanted MGE progenitor cells influence the development of acute seizure activity.
Three specific aims are proposed: (i) to develop procedures for transplantation of MGE progenitors into the adult CNS, (ii) to determine whether MGE progenitors increase inhibitory (GABAergic) function in the adult CNS, and (iii) to assess the therapeutic potential of MGE progenitor grafts against rodent seizure models. Our results promise to provide new information about the function of transplanted MGE progenitors in a host brain and may provide a direct demonstration of the potential for progenitor cells to treat intractable forms of epilepsy.
| Silbereis, John C; Nobuta, Hiroko; Tsai, Hui-Hsin et al. (2014) Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain. Neuron 81:574-87 |
| 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 |
| Southwell, Derek G; Paredes, Mercedes F; Galvao, Rui P et al. (2012) Intrinsically determined cell death of developing cortical interneurons. Nature 491:109-13 |
| Sebe, Joy Y; Baraban, Scott C (2011) The promise of an interneuron-based cell therapy for epilepsy. Dev Neurobiol 71:107-17 |
| Wang, Yanling; Dye, Catherine A; Sohal, Vikaas et al. (2010) Dlx5 and Dlx6 regulate the development of parvalbumin-expressing cortical interneurons. J Neurosci 30:5334-45 |
| Sebe, Joy Y; Looke-Stewart, Elizabeth C; Estrada, Rosanne C et al. (2010) Robust tonic GABA currents can inhibit cell firing in mouse newborn neocortical pyramidal cells. Eur J Neurosci 32:1310-8 |
| Southwell, Derek G; Froemke, Robert C; Alvarez-Buylla, Arturo et al. (2010) Cortical plasticity induced by inhibitory neuron transplantation. Science 327:1145-8 |
| Baraban, Scott C; Southwell, Derek G; Estrada, Rosanne C et al. (2009) Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice. Proc Natl Acad Sci U S A 106:15472-7 |
| Baraban, Scott C (2007) Emerging epilepsy models: insights from mice, flies, worms and fish. Curr Opin Neurol 20:164-8 |
| Alvarez-Dolado, Manuel; Calcagnotto, Maria Elisa; Karkar, Kameel M et al. (2006) Cortical inhibition modified by embryonic neural precursors grafted into the postnatal brain. J Neurosci 26:7380-9 |
