The transplantation of neuronal precursor cells is a novel and promising therapeutic approach with the potential to treat neurodegenerative disorders, such as epilepsy. Epilepsy, a neurological disorder afflicting nearly 2 million Americans, results from an increase in neuronal excitability that is often due to reduced GABAergic transmission. Recently, we demonstrated that embryonic medial ganglionic eminence (MGE) precursor cells transplanted into a postnatal rodent brain not only migrate widely in the cortex and differentiate into GABAergic interneurons, but increase synaptic inhibition recorded from neurons in the host brain. The overall goal of the proposed study is to enhance the efficacy of this transplantation strategy by transplanting embryonic MGE cells that are fated to become """"""""super"""""""" GABAergic interneurons, or interneurons that receive less GABAergic inhibition and are therefore likely to fire more action potentials in response to the same excitatory input. Prior to producing modified GABAergic interneurons, we will first characterize the inhibitory inputs received by native and grafted GABAergic interneurons to determine whether the transplantation process changes the inhibitory inputs onto grafted interneurons. Next, we will produce """"""""super"""""""" GABAergic interneurons by transplanting MGE cells from mice lacking the GABAAR 8 subunit, a subunit that mediates tonic inhibition in the brain, including in the hippocampus and cerebellum. We hypothesize that the GABAergic interneurons that differentiate from such GABAAR 6 subunit knockout (KO) mice will receive less tonic inhibition and therefore release more GABA onto the surrounding host cells. We will record GABAergic currents and assess the input-output properties from host cortical neurons that are surrounded by grafted wild-type or """"""""super"""""""" interneurons to test the hypothesis that MGE cells derived from receptor KO mice increase GABAergic inhibition in the host brain. ? ?
| 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 |
| Sebe, Joy Y; Bershteyn, Marina; Hirotsune, Shinji et al. (2013) ALLN rescues an in vitro excitatory synaptic transmission deficit in Lis1 mutant mice. J Neurophysiol 109:429-36 |
| 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 |
| 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 |
