Epilepsy affects about 2 percent of the world population and is particularly frequent in children. Relatively little is known about how epileptic seizures propagate across and recruit apparently normal cortical circuits. Given the complexity of the neocortex, where dozens of classes of excitatory and inhibitory neurons are involved in different circuit functions, it is likely that the initiation and spread of epileptic discharges are differentially controlled by specific neuronal classes. Over the last decade, we have developed an optical approach using calcium imaging from population of neurons to study neocortical circuits and to image their activation in three dimensions with 2 photon excitations. Using this strategy, we can optically detect action potentials in the somata from dozens or hundreds of neurons, image epileptiform events with single cell resolution and detect which neurons participate in different types of epileptiform events. We propose a systematic effort to understand the role of different classes of neocortical neurons in the initiation and propagation of epilepsy. We will use calcium imaging of neuronal populations during pharmacological-induced epileptiform events in neocortical slices from juvenile (P9 - P20) rat somatosensory cortex, in order to better understand the circuit mechanisms responsible for juvenile epilepsy and at the same time image the transition from interictal to ictal events. The experiments will be carried out combining whole cell recordings and biocytin reconstructions with state-of-the-art imaging techniques, including two-photon microscopy, a photodiode array and a fast cooled CCD camera. Our first goal is to characterize morphologically and physiologically the neurons involved in spontaneous and evoked interictal and ictal epileptiform events. Our final goal is to apply a novel optical probing method to reconstruct the circuitry underlying epileptiform events by revealing the postsynaptic targets that are triggered by layer 5 IB neurons, or other potentially key cell classes. The answers to these questions could have therapeutic implications for targeting specific neurons or cell layers which play a critical role in epileptiform events. Also, our results will be particularly useful in identifying the cellular and circuit mechanism responsible for the lower seizure threshold of developing and juvenile neocortex and the transition from interictal to ictal events.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS040726-01S1
Application #
6348641
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Fureman, Brandy E
Project Start
2000-09-15
Project End
2004-08-31
Budget Start
2000-09-15
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$50,000
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Goldberg, Jesse H; Tamas, Gabor; Yuste, Rafael (2003) Ca2+ imaging of mouse neocortical interneurone dendrites: Ia-type K+ channels control action potential backpropagation. J Physiol 551:49-65
Nikolenko, Volodymyr; Nemet, Boaz; Yuste, Rafael (2003) A two-photon and second-harmonic microscope. Methods 30:3-15
Aguado, Fernando; Carmona, Maria A; Pozas, Esther et al. (2003) BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2. Development 130:1267-80
Goldberg, Jesse H; Yuste, Rafael; Tamas, Gabor (2003) Ca2+ imaging of mouse neocortical interneurone dendrites: contribution of Ca2+-permeable AMPA and NMDA receptors to subthreshold Ca2+dynamics. J Physiol 551:67-78
Goldberg, Jesse H; Tamas, Gabor; Aronov, Dmitriy et al. (2003) Calcium microdomains in aspiny dendrites. Neuron 40:807-21
Hirase, Hajime; Nikolenko, Volodymyr; Goldberg, Jesse H et al. (2002) Multiphoton stimulation of neurons. J Neurobiol 51:237-47
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Bonhoeffer, Tobias; Yuste, Rafael (2002) Spine motility. Phenomenology, mechanisms, and function. Neuron 35:1019-27
Froemke, Robert C; Kumar, Vikram S; Czkwianianc, Paul et al. (2002) Analysis of multineuronal activation patterns from calcium-imaging experiments in brain slices. Trends Cardiovasc Med 12:247-52
Benavides-Piccione, Ruth; Ballesteros-Yanez, Inmaculada; DeFelipe, Javier et al. (2002) Cortical area and species differences in dendritic spine morphology. J Neurocytol 31:337-46

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