Temporal lobe epilepsy is common and difficult to treat. Our long-range research goal is to help reveal mechanisms of temporal lobe epilepsy and develop anti-epileptogenic strategies. During the last funding period we discovered in a rat model of temporal lobe epilepsy that initial loss of interneurons reduces numbers of GABAergic synapses with granule cells, but over time surviving interneurons sprout axons and develop excessive synapses. However, in epileptic dentate gyrus, although GABAergic synapses are abundant, at least some (for example, basket cell-to-granule cell synapses) are dysfunctional. During the next funding period, we propose 3 specific aims.
Aim 1 is to test whether activation of mTOR signaling pathway contributes to GABAergic axon sprouting after epileptogenic injuries. We will use GIN mice, which express green fluorescent protein (GFP) in a subset of somatostatin interneurons. Extent of axon sprouting will be measured by stereological analysis of GFP-immunoreactive axons, biocytin-labeling of axons of individual GFP-positive interneurons, and probability of recording GFP-interneuron-to-granule cell unitary IPSCs (uIPSCs).
Aim 1 will reveal whether or not mTOR signaling pathway contributes to epilepsy-related GABAergic axon sprouting. If not, based on previous findings, it would suggest mTOR pathway activation may be specific for excitatory mossy fiber sprouting. If so, it will establish a novel and innovative method for future studies to manipulate extent of GABAergic synaptogenesis and test whether it promotes or inhibits epileptogenesis.
Aim 2 is to identify mechanisms underlying increased failure rate of basket cell-to-granule cell uIPSCs after epileptogenic injuries. We will use variance-mean analysis to estimate average release probabilities and minimum numbers of release sites by recording basket cell-to-granule cell uIPSCs in slices from control and epileptic pilocarpine- treated rats. Serial-section electron microscopy will be used to measure numbers of docked vesicles at GABAergic synapses with granule cell somata in control and epileptic rats. These experiments will more precisely identify why basket cell-to-granule cell synapses are more likely to fail in epileptic tissue, which will help future attempts restore normal function at these critical synapses.
Aim 3 is to test whether hilar somatostatin interneuron-to-granule cell synapses are dysfunctional like basket cell-to-granule cell synapses after epileptogenic injuries. Approaches of Aim 2 will be used. Together, proposed experiments will advance understanding of how inhibitory synaptic transmission is affected in temporal lobe epilepsy. Ultimately, we expect data generated will help advance the long-term goal of developing anti-epileptogenic treatments.

Public Health Relevance

Many patients with epilepsy have uncontrolled spontaneous seizures that initiate in or near hippocampal dentate gyrus. Seizures might be caused by inadequate inhibition. This project will investigate in detail how and why inhibition is abnormal in dentate gyrus of a rat model of epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039110-13
Application #
8386659
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2000-04-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
13
Fiscal Year
2013
Total Cost
$332,792
Indirect Cost
$125,920
Name
Stanford University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Toyoda, Izumi; Bower, Mark R; Leyva, Fernando et al. (2013) Early activation of ventral hippocampus and subiculum during spontaneous seizures in a rat model of temporal lobe epilepsy. J Neurosci 33:11100-15
Colas, D; Chuluun, B; Warrier, D et al. (2013) Short-term treatment with the GABAA receptor antagonist pentylenetetrazole produces a sustained pro-cognitive benefit in a mouse model of Down's syndrome. Br J Pharmacol 169:963-73
Buckmaster, Paul S; Wen, Xiling (2011) Rapamycin suppresses axon sprouting by somatostatin interneurons in a mouse model of temporal lobe epilepsy. Epilepsia 52:2057-64
Zhang, Wei; Yamawaki, Ruth; Wen, Xiling et al. (2009) Surviving hilar somatostatin interneurons enlarge, sprout axons, and form new synapses with granule cells in a mouse model of temporal lobe epilepsy. J Neurosci 29:14247-56
Zhang, Wei; Buckmaster, Paul S (2009) Dysfunction of the dentate basket cell circuit in a rat model of temporal lobe epilepsy. J Neurosci 29:7846-56
Buckmaster, Paul S; Ingram, Elizabeth A; Wen, Xiling (2009) Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci 29:8259-69
Thind, Khushdev K; Ribak, Charles E; Buckmaster, Paul S (2008) Synaptic input to dentate granule cell basal dendrites in a rat model of temporal lobe epilepsy. J Comp Neurol 509:190-202
Kumar, Sanjay S; Buckmaster, Paul S (2007) Neuron-specific nuclear antigen NeuN is not detectable in gerbil subtantia nigra pars reticulata. Brain Res 1142:54-60
Buckmaster, Paul S; Alonso, Angel; Canfield, Don R et al. (2004) Dendritic morphology, local circuitry, and intrinsic electrophysiology of principal neurons in the entorhinal cortex of macaque monkeys. J Comp Neurol 470:317-29
Austin, Jenifer E; Buckmaster, Paul S (2004) Recurrent excitation of granule cells with basal dendrites and low interneuron density and inhibitory postsynaptic current frequency in the dentate gyrus of macaque monkeys. J Comp Neurol 476:205-18

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