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Inhibitory Interneurons and Epilepsy: Cellular Mechanisms and Potential Therapies

  • Author(s): Jones, Daniel
  • Advisor(s): Baraban, Scott C
  • Schnapf, Julie
  • et al.
Abstract

Epilepsy is a neurological disorder that affects millions of people worldwide, and in it simplest form, is thought to result from an imbalance between excitation and inhibition in the nervous system. Defects in inhibitory systems of the cortex and hippocampus, which can range from disruptions in neural development to impairments in GABA-mediated synaptic transmission, have been associated with epilepsy. In these studies, I explore the complex relationship between inhibitory interneurons and epilepsy in three different systems: (1) a mouse model of type-1 Lissencephaly, in which interneurons are present in normal numbers, but are displaced into inappropriate hippocampal layers; (2) Dlx1 knockout mice, in which certain populations of interneurons undergo programmed cell death within the first month of life; (3) wild-type mice that have received a graft of interneuron precursor cells from the medial ganglionic eminence. I report significant reorganizations in inhibitory (and excitatory) circuits in these mouse models of epilepsy, and further demonstrate that progenitor cells grafted into the postnatal brain can be used to generate new inhibitory interneurons. Taken together, this body of work illustrates the important role played by inhibitory neurons in regulating network excitability, and highlights the potential of neural progenitor cell transplantation as an effective treatment to reduce seizures.

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