Extramural Research Programs in the Neurosciences and Neurological Disorders: Contribution of Adult Neurogenesis to Epileptogenesis and Recovery After TBI

Abstract More than one million people are treated medically each year in the United States after sustaining a head injury. Traumatic brain injury (TBI) is often accompanied by the delayed development of posttraumatic epilepsy (PTE), for which there are few effective therapies. Although clinical association between TBI and epilepsy is well documented, treatments designed to prevent PTE have been largely unsuccessful. Among the most promising antiepileptogenic treatments reported to date center on inhibition of the mammalian (mechanistic) target of rapamycin (mTOR) pathway. mTOR is activated after TBI and seizures, and it’s activity regulates a variety of cellular activities, including growth, proliferation, survival, and death, especially in developing neurons. Inhibiting mTOR activity has shown promise for altering the progression of epileptogenesis in rodent models of epilepsy, including PTE, but several caveats have also been acknowledged, specifically: Suppression of mTOR post-TBI has been proposed to prevent epileptogenesis, whereas mTOR activation has been proposed as a means of diminishing injury and improving cognitive recovery after TBI in patients. Advancing mTOR modulation treatment post-TBI is hampered by fundamental gaps in understanding how mTOR exerts its effects. Since mTOR regulates many processes involved in both post-injury repair and epileptogenesis, a better understanding of the functional effects of post-injury mTOR modulation is necessary to better understand its multiple, and perhaps paradoxical effects long-term after TBI. This proposal will use the controlled cortical impact (CCI) model of TBI, which results in cell loss, increased neuron proliferation, synaptic reorganization in the dentate gyrus, and delayed development of spontaneous seizures (i.e., epileptogenesis) to study effects of both negative and positive regulation of mTOR on epileptogenesis and cognitive recovery after brain injury. The overarching hypothesis is that early mTOR activation is neuroprotective, including in neural progenitor cells in the dentate gyrus, thus contributing to post-TBI recovery, whereas mTOR inhibition suppresses adult neurogenesis and PTE development. A combination of histological, molecular, behavioral, and electrophysiological techniques will be used to address three aims designed to identify the role of adult born dentate granule cells and the effects of mTOR modulation on adult neurogenesis after TBI: 1) Determine effects of mTOR modulation on functional cellular outcomes related to adult neurogenesis after TBI Determine effects of mTOR modulation on neurogenesis in the dentate gyrus after TBI; 2) Determine effects of TBI on the functional synaptic organization of dentate granule cells; and 3) Determine how adult born dentate granule cell contribution to functional recovery and seizures after TBI. A mechanistic understanding of how adult born neurons contribute to DGC circuitry and how mTOR modulation alters the circuitry of these neurons after CCI will be developed in the context of both cognitive recovery after TBI and development of PTE. A better understanding of the contribution of adult born neurons to injury recovery and epileptogenesis after TBI will facilitate the development of treatments to prevent PTE.