EXCEED THE SPACE PR_tBEB.. The proposed experiments use an in vivo model for partial epilepsy of temporal lobe origin to test hypotheses regarding the spread of seizure into normally functioning cortex from areas with epileptogenic abnormalities. Studies in vitro have identified many processes that are potentially involved; determining which of these are actually involved and how they contribute will require studies in intact animals that build on findings from in vitro analysis. The experiments will be performed on rat piriform cortex (PC) where partial seizures that secondarily generalize can be readily recruited in behaving animals by activity emanating from a small disinhibited focus. This same process can be duplicated under urethane anesthesia, enabling analytical study in vivo. Electrographic seizures are recruited when normal PC and adjoining limbic cortex are subjected to several seconds of low rate (3-4 Hz) rhythmic excitatory volleys generated by interictal-like discharges in a distant disinhibited focus. A detailed working hypothesis has been developed for the cascade of processes that underlies this transformation. Features of the hypothesis include: (1) K* plays a causal role for seizure spread into normal cortex (despite evidence to the contrary for seizure initiation). (2) Mechanisms for recruitment of seizure in hippocampus differ from those in most other limbic areas including PC. These stem from the lack of an inwardly rectifying cr channel (CIC-2) that regulates somatic-region CI- in hippocampal pyramidal cells but not in PC and many other limbic areas, and glial-like inwardly-rectifying K channels that are weak or absent in hippocampal neurons but present in PC and other limbic areas. (3) Based on our findings from current source-density (CSD) analysis and transmembrane potential recordings in vivo, we propose that ephaptic-field transmission plays a central role in the generation of ictal activity by allowing high-rate, self-sustained discharges to occur after synaptic transmission is attenuated by depletion of docked synaptic vesicles and other factors. A key method is CSD analysis with a 22-site silicon probe that allows rapidly-evolving dendritic-region as well as somatic-region membrane currents to be visualized. Propagation of ephaptic-field driven discharges will be studied using new approaches for 2- and 3- dimensional CSD analysis. These experiments will provide essential information about the spread of epileptic activity into normal cortex, and clues concerning how this spread can be curtailed. PERFORMANCE SiTE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS019865-17
Application #
6823264
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Fureman, Brandy E
Project Start
2002-12-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
17
Fiscal Year
2005
Total Cost
$386,413
Indirect Cost
Name
University of Wisconsin Madison
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Feig, S L; Haberly, L B (2011) Surface-associated astrocytes, not endfeet, form the glia limitans in posterior piriform cortex and have a spatially distributed, not a domain, organization. J Comp Neurol 519:1952-69
Howe, Mark W; Feig, Sherry L; Osting, Susan M K et al. (2008) Cellular and subcellular localization of Kir2.1 subunits in neurons and glia in piriform cortex with implications for K+ spatial buffering. J Comp Neurol 506:877-93
Neville, Kevin R; Haberly, Lewis B (2003) Beta and gamma oscillations in the olfactory system of the urethane-anesthetized rat. J Neurophysiol 90:3921-30
Ekstrand, J J; Domroese, M E; Johnson, D M et al. (2001) A new subdivision of anterior piriform cortex and associated deep nucleus with novel features of interest for olfaction and epilepsy. J Comp Neurol 434:289-307
Ekstrand, J J; Domroese, M E; Feig, S L et al. (2001) Immunocytochemical analysis of basket cells in rat piriform cortex. J Comp Neurol 434:308-28
Demir, R; Haberly, L B; Jackson, M B (2001) Epileptiform discharges with in-vivo-like features in slices of rat piriform cortex with longitudinal association fibers. J Neurophysiol 86:2445-60
Demir, R; Haberly, L B; Jackson, M B (1999) Sustained and accelerating activity at two discrete sites generate epileptiform discharges in slices of piriform cortex. J Neurosci 19:1294-306
Demir, R; Haberly, L B; Jackson, M B (1999) Sustained plateau activity precedes and can generate ictal-like discharges in low-Cl(-) medium in slices from rat piriform cortex. J Neurosci 19:10738-46
Behan, M; Haberly, L B (1999) Intrinsic and efferent connections of the endopiriform nucleus in rat. J Comp Neurol 408:532-48
Kapur, A; Haberly, L B (1998) Duration of NMDA-dependent synaptic potentiation in piriform cortex in vivo is increased after epileptiform bursting. J Neurophysiol 80:1623-9

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