Cellular mechanisms of Pathological high frequency oscillations (pHFO) In Vitro

University Of California Los Angeles, Los Angeles CA

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Abstract

High-frequency oscillations (HFO) including Ripples are associated with well-defined neuronal events and[unreadable] are commonly recorded in certain parts of the mesial temporal lobe (MTL) such as the CA1 region and the[unreadable] subiculum. Conspicuously, such oscillations cannot be observed under normal conditions in the dentate[unreadable] gyrus, but this structure will readily produce HFO during the process of epileptogenesis. Because of their[unreadable] tight association with MTL epilepsy (MTLE), HFO of the dentate gyrus should always be considered to be[unreadable] pathological. Moreover, the MTLE-associated HFO observed with high incidence in the CA1 and subiculum[unreadable] may also significantly differ from the HFO seen under normal conditions. The MTLE-associated[unreadable] pathological HFO (pHFO) consisting of pathological Ripples (pR) in the range of 100-200 Hz and Fast[unreadable] Ripples (FR) in the range of 200-500 Hz in epileptogenic structures reflect fundamental neuronal mechanisms[unreadable] responsible for the development of epilepsy and the generation of spontaneous seizures. Since inhibitory[unreadable] interneurons play a prominent role in the manifestation of these synchronous events, the immediate research[unreadable] objectives of this proposal consist of a series of tightly integrated parallel in vitro studies in slices from[unreadable] MTLE patients and from an experimental animal model of this condition: the pilocarpine-treated (PILO)[unreadable] mouse. The goals are i) to identify and characterize the alterations in principal neurons and in specific[unreadable] subclasses of interneurons leading to re-assembly into pathological networks capable of generating pHFO; ii)[unreadable] to examine the effects of ablation and stimulation of specific interneurons on pHFO generation. The overall[unreadable] hypothesis is that secondary to changes in intrinsic neuronal excitability and interconnections during the[unreadable] process of epileptogenesis, patterns of activation and spiking, that differ from control conditions, in specific[unreadable] interneurons and principal cells contribute to the generation of pHFO. In some MTL structures (e.g., CA1[unreadable] and subiculum), the cell assemblies involved in pHFO generation may not be the same as those active during[unreadable] physiological Ripple activity. In the dentate gyrus, where normally there are no HFO generating cell[unreadable] assemblies, a pathological reorganization of specific interneurons and dentate gyrus granule cells (DGGC)[unreadable] into epileptic cell assemblies capable of generating pHFO is a critical component of epileptogenesis and may[unreadable] constitute.one of the earliest events of this pathological process. Thus, identifying the progression, targets,[unreadable] and mechanisms of such pathological cell assemblies will yield important clues for preventing and possibly[unreadable] even reversing the epileptogenic process.