Inhibitory interneurons perform important roles in regulating cortical network function, and their loss is associated with a number of neurological and psychiatric disorders. As such, transplantation of inhibitory neuronal progenitor cells might be a useful method to restore deficits in inhibition in the diseased brain. Our laboratory recently demonstrated that progenitor cells derived from the medial ganglionic eminence can migrate, differentiate into GABAergic interneurons, and suppress spontaneous seizures in a developmental epilepsy model. Despite these recent advances in transplantation strategies, the effect of inhibitory neural progenitor cell subtypes derived from other regions of the embryonic telencephalon on existing host circuitry remains largely unknown, especially after transplant into the adult brain. In this postdoctoral fellowship proposal, I will determine how GABA-progenitor cells derived from the caudal ganglionic eminence alter inhibitory circuitry after transplant into the adult dentate gyrus.
Two specific aims are proposed, to determine: (1) progenitor cell migration and phenotypes of GABAergic subtypes generated after transplant into the adult hippocampus, and (2) how these new interneurons alter existing synaptic circuitry in the dentate gyrus. Electrophysiological results will be correlated with cellular, molecular, and anatomical characteristics. This study will provide detailed information about the synaptic connectivity of GABAergic progenitor cells after transplant into the adult brain.
A number of neurological disorders involve the loss of inhibitory interneurons, and a transplantation method to generate new cortical interneuron subtypes in affected brain regions might be a useful therapeutic approach. I will determine how embryonic inhibitory neural progenitor cells integrate into existing circuits after transplant into the adult hippocampus. By determining the synaptic connections formed by these cells, we will be able to develop methods for cortical interneuron replacement therapies to restore normal function in the human diseased brain.
|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|
|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|