Cellular Mechanisms of Pathological high frequency Oscillations In Vivo

$186,550P01FY2007NSNIH

University Of California Los Angeles, Los Angeles CA

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Abstract

The objective of this proposal is to investigate the neuronal substrates of pathological high frequency oscillations (pHFO). Recently we described the occurrence of pHFO in the dentate gyrus, during the latent period, in rats that develop recurrent spontaneous seizures after kainic acid (KA) induced status epilepticus. Power spectral analysis indicated two types of pHFO: pathological Ripples (pR) (100-200 Hz) and Fast Ripples (FR) (250-500 Hz). These oscillations appear to reflect changes in neuronal organization leading to epilepsy after an initial precipitating event. We propose to carry out acute extracellular recordings of neurons followed by juxtacellular labeling of these neurons and visualization of the neuronal type and their target areas, in rats dentate gyrus before and after pilocarpine (PILO) induced status epilepticus, and after spontaneous seizures are established. We also will carry out voltage depth profile analysis to localize the sources and sinks of pHFO and normal ripples in CA1, EC and subiculum. We are asking the following questions i) Are the neuronal mechanisms of pR the same as those of normal Ripple oscillations or are they the same as FR? ii) If they represent the same mechanisms as FR, does the bimodal frequency distribution during epileptogenesis indicate involvement of different neuronal networks? iii) Is there a decrease in pR and increase in FR after spontaneous seizures are established and, if so, why? and iv) Are some Ripple frequency oscillations recorded in hippocampus, entorhinal cortex, and other parahippocampal structures during epileptogenesis, and after spontaneous seizures are established, pathological? Elucidation of the neuronal substrates of pHFO will suggest further experiments to understand how these neuronal disturbances might be involved in epileptogenesis, and in seizure generation. It is anticipated that this research will ultimately provide informationthat will lead to new approaches to prevent and treat epilepsy and its consequences.

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