 |
|
Degrees:
|
M.D.
|
|
Department:
|
Neurology
|
|
Research Center:
|
|
|
Keywords:
|
epilepsy, seizures, epileptogenesis, hippocampus, dentate gyrus,
plasticity, selective vulnerability, growth factors, neurotrophins, excitotoxicity, chemotropic factors, axon guidance molecules, neurogenesis
|
|
Research Description:
|
Basic Mechanisms of Epileptogenesis
One of the intriguing features of focal epilepsy is the time-delay between an initial traumatic event and subsequent network hyperexcitability. Our laboratory is interested in understanding the biological processes that underlie this transition from a normal to abnormal network in the mature CNS. Knowledge about these mechanisms will hopefully lead to the design of new therapies that could prevent the development of a seizure focus in at-risk patients.
Using the hippocampus as a model system, our studies are concentrating on two particular changes in neural networks that are associated with hyperexcitability following CNS injury. The first is the selective loss of a subpopulation of dentate gyrus neurons (hilar interneurons) which appear to have an important role in governing the excitability of dentate granule cells. We have studied the vulnerability of these cells to various forms of injury, and are interested in the role of certain intracellular proteins (e.g. calcium-binding proteins) which may affect the relative susceptibility of these neurons to injury.
The second area of study concerns the axonal reorganization that occurs in the dentate gyrus following different forms of hippocampal injury. Various neuronal projections within the hippocampus can be observed to "sprout" during the weeks to months after injury, and the new, aberrant synaptic contacts are predicted to alter dentate gyrus excitability. We are using a combination of approaches to identify the factors that are part of the molecular algorithm underlying sprouting.
These include studies of:
1) the temporal and spatial expression of neurotrophins during sprouting,
2) the effects of trophic and axon guidance factors on primary and explant cultures of dentate granule cells,
3) the changes in neuronal gene expression during sprouting as identified by differential cloning, and
4) the modification of sprouting in vivo by infusion of reagents that alter neuronal excitability or interact with molecular factors that may influence axon growth and targeting.
|
|
Web Page:
|
|
|
Selected Publications:
|
1. Sloviter RS, Lowenstein DH. Heat shock protein expression in vulnerable cells of the rat hippocampus as an indicator of excitation-induced neuronal stress. Journal of Neuroscience 12:3004-3009, 1992.
2. Lowenstein DH, Thomas MJ, Smith DEJ, McIntosh TK. Selective vulnerability of dentate hilar neurons following traumatic brain injury: A potential mechanistic link between head trauma and disorders of the hippocampus. Journal of Neuroscience 12:4846-4853, 1992.
3. Lowenstein DH, Seren S, Longo FM. Prolonged increases in neurotrophic activity associated with kainate-induced synaptic reorganization. Neuroscience 56:597-604, 1993.45.
4. Holtzman DM, LOWENSTEIN DH. Selective inhibition of axon outgrowth by antibodies to NGF in a model of temporal lobe epilepsy. Journal of Neuroscience 15:7062-7070, 1995.
5. LOWENSTEIN DH, Arsenault L. The effects of growth factors on the survival and differentiation of cultured dentate gyrus neurons. Journal of Neuroscience 16:1759-1769, 1996.
|
|
Prerequisite for student research:
|
|
|
|
|
