The long-term objective of this research is to gain a better understanding of the basic mechanisms of epilepsy. The perforant path stimulation (PPS) model will be used to determine the anatomical and physiological significance of basal dendrites on dentate granule cells following status epilepticus. In this model, mossy fiber sprouting occurs and provides a basis for the formation of recurrent excitatory connections among granule cells. The discovery of basal dendrites on granule cells that enter the hilus where mossy fibers are concentrated may provide an additional postsynaptic target for mossy fibers, and it could increase the amount of recurrent excitation. We will test the hypothesis that hippocampal status epilepticus induces the formation of basal dendrites on dentate gyrus granule cells that become integrated in to hippocampal circuitry. The first specific aim will determine whether seizures are a sufficient stimulus to induce the formation of basal dendrites on granule cells. An array of staining methods will be used to demonstrate the time course of basal dendrite formation in the PPS model and determine whether seizures in three other models cause basal dendrite formation. In addition, this aim will determine if hilar cell death without status epilepticus is a sufficient stimulus to induce basal dendrite formation. Global ischemia will be used to cause hilar neuronal loss.
The second aim will determine if the basal dendrites on granule cells from PPS rats are anatomically integrated into hippocampal circuitry and receive identified synaptic inputs. Electron microscopic preparations will be used to identify the basal dendrites of granule cells to determine whether they are postsynaptic to mossy fibers and GABAergic axon terminals.
The third aim will determine if the basal dendrites on granule cells from PPS rats are functionally integrated into hippocampal circuitry. Specifically, do basal dendrites possess functional receptors for excitatory and inhibitory neurotransmitters and does activation of these receptors affect somatic excitability of the granule cells and their ability to generate action potentials? Patch-clamp recordings from the somata or basal dendrites will be made after identifying granule cells with these dendrites using DiI loading in slices from epileptic rats.
The fourth aim will determine whether basal dendrites sprout from mature granule cells or if they are immature dendrites typically observed for newly generated granule cells. These studies will provide new information about a novel neuroplastic change observed in the hippocampal dentate gyrus o rats with temporal lobe epilepsy, and are relevant to epileptic humans who have double the number of granule cells with basal dendrites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038331-04
Application #
6540057
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Fureman, Brandy E
Project Start
1999-07-01
Project End
2005-02-28
Budget Start
2002-07-01
Budget End
2005-02-28
Support Year
4
Fiscal Year
2002
Total Cost
$378,158
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Ribak, Charles E (2017) An abnormal GABAergic system in the inferior colliculus provides a basis for audiogenic seizures in genetically epilepsy-prone rats. Epilepsy Behav 71:160-164
Díaz-Cintra, Sofia; Xue, Baogang; Spigelman, Igor et al. (2009) Dentate granule cells form hilar basal dendrites in a rat model of hypoxia-ischemia. Brain Res 1285:182-7
Shapiro, Lee A; Perez, Zachary D; Foresti, Maira L et al. (2009) Morphological and ultrastructural features of Iba1-immunolabeled microglial cells in the hippocampal dentate gyrus. Brain Res 1266:29-36
Ribak, Charles E; Shapiro, Lee A; Perez, Zachary D et al. (2009) Microglia-associated granule cell death in the normal adult dentate gyrus. Brain Struct Funct 214:25-35
Shapiro, Lee A; Ng, Kwan; Zhou, Qun-Yong et al. (2009) Subventricular zone-derived, newly generated neurons populate several olfactory and limbic forebrain regions. Epilepsy Behav 14 Suppl 1:74-80
Toni, Nicolas; Laplagne, Diego A; Zhao, Chunmei et al. (2008) Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci 11:901-7
Shapiro, Lee A; Ribak, Charles E; Jessberger, Sebastian (2008) Structural changes for adult-born dentate granule cells after status epilepticus. Epilepsia 49 Suppl 5:13-8
Jacquin, Mark F; Arends, Joop J A; Xiang, Chuanxi et al. (2008) In DRG11 knock-out mice, trigeminal cell death is extensive and does not account for failed brainstem patterning. J Neurosci 28:3577-85
Shapiro, Lee A; Wang, Lulu; Ribak, Charles E (2008) Rapid astrocyte and microglial activation following pilocarpine-induced seizures in rats. Epilepsia 49 Suppl 2:33-41
Ribak, Charles E; Shapiro, Lee A (2007) Dendritic development of newly generated neurons in the adult brain. Brain Res Rev 55:390-4

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