Our long-term goal is to help elucidate mechanisms of temporal lobe epilepsy and develop more effective treatments for patients. During the previous funding period we discovered increased activity of dentate granule cells beginning minutes before spontaneous seizures in a rat model of temporal lobe epilepsy. We now propose to further evaluate the entorhinal-hippocampal circuit to localize the site(s) of earliest preictal activity (Aim 1), test potential mechanisms of seizure initiation (Aim 2), and determine whether unit recording can be used to predict seizures in real time (Aim 3).
Aim 1 is to use tetrodes to record unit activity in dentate gyrus, CA1, CAS, subiculum, and medial entorhinal cortex (layers II, III, and V/VI) in epileptic pilocarpine- treated rats as they experience spontaneous seizures. Electrographic seizure onset will be standardized by objective methods applied to field potential recordings from dentate gyrus in all cases. Neuron firing rates will be plotted with respect to seizure onset and analyzed to determine whether and when they significantly exceed baseline levels. The region(s) displaying earliest preictal unit activity will be identified as a potential site of seizure initiation.
Aim 2 is to begin testing hypotheses of seizure initiation: that in epileptic rats granule cells fail to provide sufficient excitatory synaptic drive to GABAergic interneurons (Experiment 2a) and that within the aberrant, recurrent, excitatory dentate circuit granule cells with basal dendrites are hyper- connected elements and therefore potential initiators or propagators of seizure activity (Experiment 2b). In collaboration with John Huguenard we will use laser scanning photo-uncaging of glutamate to focally activate granule cells in hippocampal slices while obtaining whole cell recordings of evoked excitatory postsynaptic currents in interneurons (Experiment 2a) and granule cells (Experiment 2b), which will be labeled with biocytin to determine whether they have basal dendrites or not.
Aim 3 is to develop classifier algorithms and use on-line multi-unit recording and analysis to predict spontaneous seizures of epileptic pilocarpine-treated rats in real time. Broadband recordings of prolonged periods of interictal and preictal activity will be obtained, evaluated, and made available to other investigators. The proposed experiments will help reveal underlying causes of temporal lobe epilepsy by beginning to localize the brain region(s) displaying earliest pre-seizure activity and test potential mechanisms of seizure initiation. In addition, we will attempt for the first time to predict seizures by monitoring action potential firing rates. If successful in epileptic rats, this method may eventually lead to seizure prediction devices for patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS012151-36
Application #
8292157
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
2012-11-30
Budget Start
2011-07-01
Budget End
2012-11-30
Support Year
36
Fiscal Year
2011
Total Cost
$294,367
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Gu, Feng; Parada, Isabel; Shen, Fran et al. (2017) Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis. Neurobiol Dis 108:100-114
Takahashi, D Koji; Gu, Feng; Parada, Isabel et al. (2016) Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma. Neurobiol Dis 91:166-81
Prince, David A (2014) How do we make models that are useful in understanding partial epilepsies? Adv Exp Med Biol 813:233-41
Tani, Hiroaki; Dulla, Chris G; Farzampour, Zoya et al. (2014) A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. Neuron 81:888-900
Jin, Xiaoming; Jiang, Kewen; Prince, David A (2014) Excitatory and inhibitory synaptic connectivity to layer V fast-spiking interneurons in the freeze lesion model of cortical microgyria. J Neurophysiol 112:1703-13
Mantoan Ritter, Laura; Golshani, Peyman; Takahashi, Koji et al. (2014) WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. Epilepsia 55:1693-702
Dulla, C G; Tani, H; Brill, J et al. (2013) Glutamate biosensor imaging reveals dysregulation of glutamatergic pathways in a model of developmental cortical malformation. Neurobiol Dis 49:232-46
Ma, Yunyong; Ramachandran, Anu; Ford, Naomi et al. (2013) Remodeling of dendrites and spines in the C1q knockout model of genetic epilepsy. Epilepsia 54:1232-9
Dewolfe, Jennifer L; Malow, Beth; Huguenard, John et al. (2013) Sleep and epilepsy: a summary of the 2011 merritt-putnam symposium. Epilepsy Curr 13:42-9
Buckmaster, Paul S; Haney, Megan M (2012) Factors affecting outcomes of pilocarpine treatment in a mouse model of temporal lobe epilepsy. Epilepsy Res 102:153-9

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