Recurrent mossy fiber growth in the hippocampal dentate gyrus is a unique feature of temporal lobe epilepsy. The formation of new mossy fiber-granule cell connections greatly expands a monosynaptic recurrent excitatory circuit that is normally very limited. It has been proposed that the circuit contributes to epileptogenesis by diminishing the resistance of the dentate gyrus to seizure propagation. The objective of this project is to discover the conditions under which these synapses are most likely to facilitate seizure propagation and to identify synaptic properties that could serve as therapeutic targets. Little is currently known about the physiology and pharmacology of mossy fiber- granule cell synapses; the proposed project is intended to fill this gap. Pilocarpine-treated rats, which become epileptic and also develop a consistently dense recurrent mossy fiber pathway, will be used to investigate three aspects of synaptic function. First, the characteristics of and the conditions needed to provoke three forms of presynaptic plasticity identified at mossy fiber-CA3 pyramidal cell synapses will be determined for the recurrent mossy fiber pathway. These studies will define the patterns of granule cell activity that are most likely to drive strong monosynaptic feedback excitation. Because preliminary results suggest that pilocarpine-induced status epilepticus enhances the contribution of NMDA receptors to the synaptic response, another study will determine whether mossy fiber-granule cell synapse on the epileptic brain exhibit an NMDA-dependent form of long term potentiation. Second, the involvement of kainate and metabotropic glutamate receptors to the synaptic response will be analyzed. One goal of this study is to evaluate these receptors as potential therapeutic targets of drugs directed against the recurrent mossy fiber pathway. Finally, the ability of zinc released by mossy fiber stimulation to alter GABA/A, NMDA, AMPA and kainate receptor function in granule cells will be assessed with use of agonists uncaged by highly focused ultraviolet light. This study will determine whether recurrent mossy fibers might also influence seizures through modification of postsynaptic glutamate receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038108-02
Application #
6151620
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Fureman, Brandy E
Project Start
1999-02-01
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
2
Fiscal Year
2000
Total Cost
$272,853
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Cameron, Michael C; Zhan, Ren-Zhi; Nadler, J Victor (2011) Morphologic integration of hilar ectopic granule cells into dentate gyrus circuitry in the pilocarpine model of temporal lobe epilepsy. J Comp Neurol 519:2175-92
Zhan, Ren-Zhi; Timofeeva, Olga; Nadler, J Victor (2010) High ratio of synaptic excitation to synaptic inhibition in hilar ectopic granule cells of pilocarpine-treated rats. J Neurophysiol 104:3293-304
Zhan, Ren-Zhi; Nadler, J Victor (2009) Enhanced tonic GABA current in normotopic and hilar ectopic dentate granule cells after pilocarpine-induced status epilepticus. J Neurophysiol 102:670-81
Nadler, J Victor; Tu, Bin; Timofeeva, Olga et al. (2007) Neuropeptide Y in the recurrent mossy fiber pathway. Peptides 28:357-64
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
Feng, Li; Molnar, Peter; Nadler, J Victor (2003) Short-term frequency-dependent plasticity at recurrent mossy fiber synapses of the epileptic brain. J Neurosci 23:5381-90
Nadler, J Victor (2003) The recurrent mossy fiber pathway of the epileptic brain. Neurochem Res 28:1649-58
Molnar, P; Nadler, J V (2001) Synaptically-released zinc inhibits N-methyl-D-aspartate receptor activation at recurrent mossy fiber synapses. Brain Res 910:205-7
Molnar, P; Nadler, J V (2001) Lack of effect of mossy fiber-released zinc on granule cell GABA(A) receptors in the pilocarpine model of epilepsy. J Neurophysiol 85:1932-40