The long term goal of this laboratory is to understand the pathophysiology of limbic epilepsy in molecular terms. The two objectives of this proposal represent related but distinct approaches to this goal Kindling is the most widely studied animal model of limbic epilepsy. Enhanced function of excitatory synapses using the NMDA subtype of glutamate receptor may contribute to the expression of the enduring hyperexcitability of kindling. CA3 pyramidal cells of the kindled hippocampus exhibit a selective and longlasting increased sensitivity to NMDA as evident in an NMDA-evoked depolarization. At least part of the molecular basis of this increased sensitivity appears to be a strikingly increased density (greater than 10% 1) of a """"""""novel"""""""" NMDA receptor (NMDARk), identified during the present funding period. We think that NMDARk is part of the molecular basis of the lasting hyperexcitability of the kindled brain. Our first objective is to elucidate the molecular basis of NMDARk. The molecular cloning of multiple cDNAs encoding NMDA receptor subunits has provided both reagents and insights with which to pursue this inquiry. Since the affinity of ligands for neurotransmitter receptors can be differentially modulated by alterations of either subunit composition or phosphorylation, we hypothesize that NMDARk reflects a receptor bearing one or both of these molecular modifications. We will test these alternative hypotheses using antibodies specific to distinct subunits of the NMDA receptor expressed in the hippocampus. Understanding the molecular nature of NMDARk should facilitate elucidating how NMDARk affects the excitability of CA3 pyramidal cells, where (in addition to CA3) in a kindled brain NMDARk is present, how nMDARk contributes to the hyperexcitability of a kindled animal and, ultimately, of human limbic epilepsy. We have unexpectedly-discovered that transgenic mice carrying a null mutation of the alpha-subunit of calcium calmodulin kinase II gene exhibit limbic epilepsy. This model recapitulates a number of aspects of human limbic epilepsy including spontaneous seizures, axonal sprouting of hippocampal granule cell axons in the supragranular region of the dentate, and dispersion of the granule cell layer. The link to a single, identified gene focuses the search for the underlying mechanisms. The second objective of this proposal is to characterize this new model and thereby obtain information helpful for mechanistic analyses to be pursued by Drs. Dingledine and Nadler.

Project Start
1999-05-01
Project End
2000-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
18
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Crooks, Kristy R; Kleven, Daniel T; Rodriguiz, Ramona M et al. (2010) TrkB signaling is required for behavioral sensitization and conditioned place preference induced by a single injection of cocaine. Neuropharmacology 58:1067-77
Nadler, J Victor; Tu, Bin; Timofeeva, Olga et al. (2007) Neuropeptide Y in the recurrent mossy fiber pathway. Peptides 28:357-64
Jiao, Yiqun; Nadler, J Victor (2007) Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy: correlation of cell loss with mossy fiber sprouting. Exp Neurol 205:569-82
He, X-P; Butler, L; Liu, X et al. (2006) The tyrosine receptor kinase B ligand, neurotrophin-4, is not required for either epileptogenesis or tyrosine receptor kinase B activation in the kindling model. Neuroscience 141:515-20
Bausch, Suzanne B; He, Shuijin; Petrova, Yelena et al. (2006) Plasticity of both excitatory and inhibitory synapses is associated with seizures induced by removal of chronic blockade of activity in cultured hippocampus. J Neurophysiol 96:2151-67
Tu, B; Jiao, Y; Herzog, H et al. (2006) Neuropeptide Y regulates recurrent mossy fiber synaptic transmission less effectively in mice than in rats: Correlation with Y2 receptor plasticity. Neuroscience 143:1085-94
Timofeeva, Olga; Nadler, J Victor (2006) Facilitation of granule cell epileptiform activity by mossy fiber-released zinc in the pilocarpine model of temporal lobe epilepsy. Brain Res 1078:227-34
Tu, Bin; Timofeeva, Olga; Jiao, Yiqun et al. (2005) Spontaneous release of neuropeptide Y tonically inhibits recurrent mossy fiber synaptic transmission in epileptic brain. J Neurosci 25:1718-29
Danzer, Steve C; McNamara, James O (2004) Localization of brain-derived neurotrophic factor to distinct terminals of mossy fiber axons implies regulation of both excitation and feedforward inhibition of CA3 pyramidal cells. J Neurosci 24:11346-55
Danzer, Steve C; He, Xiaoping; McNamara, James O (2004) Ontogeny of seizure-induced increases in BDNF immunoreactivity and TrkB receptor activation in rat hippocampus. Hippocampus 14:345-55

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