Temporal lobe epilepsy is the most common form of epilepsy in adults. Currently available anti-epileptic drugs often have significant and debilitating side-effects, and temporal lobe epilepsy frequently becomes resistant to drug therapy, presenting an enormous social and medical problem. The central idea behind the proposed research is that it may be possible to achieve seizure control by transiently inhibiting, only at critical moments, the activity of a low number of unique neurons that may be primarily responsible to triggering seizures in the limbic system. Our recent large-scale computational modeling studies have shown that rare, abnormal, super- connected, hub-like neurons may play a key role in seizure initiation. Subsequently, such hub cells have been demonstrated in the healthy developing hippocampus, and it has been shown that modulation of single hub cells in slices can block the spontaneous bursting activity of the entire network. Here we propose to use novel optogenetic approaches to selectively inhibit abnormal hub-like cells in the dentate gyrus and entorhinal cortex of epileptic adult mice in vivo in order to prevent the hyper-activation of the commissural-associational and temporo-ammonic pathways within the entorhino-hippocampal network specifically at the onset of spontaneous recurrent seizures. Because the manipulation will affect only a few cells in the entire limbic system in a temporally selective manner, effective seizure control may be achieved with minimal effects on the normal information processing of the circuit. If successful, the proposed research will demonstrate a fundamentally novel approach to achieving the goal of "no seizures, no side-effects" for the treatment of epilepsy.

Public Health Relevance

Many patients with temporal lobe epilepsy have repeated spontaneous seizures that cannot be controlled with existing drug therapies. Spontaneous seizures may be caused by persistently altered circuits that emerge after precipitating insults. The project will determine whether transiently inhibiting pathologically super-connected neurons using cutting-edge optical techniques can prevent the generation of seizures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS074702-04
Application #
8624720
Study Section
Special Emphasis Panel (ZNS1-SRB-B (24))
Program Officer
Fureman, Brandy E
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$292,511
Indirect Cost
$94,511
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Armstrong, Caren; Krook-Magnuson, Esther; Oijala, Mikko et al. (2013) Closed-loop optogenetic intervention in mice. Nat Protoc 8:1475-93
Krook-Magnuson, Esther; Armstrong, Caren; Oijala, Mikko et al. (2013) On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat Commun 4:1376
Krook-Magnuson, Esther; Varga, Csaba; Lee, Sang-Hun et al. (2012) New dimensions of interneuronal specialization unmasked by principal cell heterogeneity. Trends Neurosci 35:175-84
Soltesz, Ivan (2011) The Brain Prize 2011: From Microcircuit Organization to Constellations of Brain Rhythms. Trends Neurosci 34:501-3