Robert S. Sloviter - US grants

DESCRIPTION (provided by applicant): Temporal lobe epilepsy is a common and devastating neurological disorder that is often resistant to treatment. Although spontaneous epileptic seizures are believed to arise from an altered circuit within the temporal lobe, the nature of the causal network defect remains unidentified. The proposed experimental studies have been designed to elucidate the normal functional and structural organization of the hippocampus, with particular emphasis on the lamellar organization of this epileptogenic brain region. One hypothesis suggests that hippocampal segments are functionally separated from adjacent segments by translamellar inhibitory mechanisms, and that the breakdown of inhibitory barriers causes the formation of hyperexcitable "supersegments." This hypothesis will be addressed in a series of studies designed to demonstrate translamellar inhibition electrophysiologically, to identify the neurons that form the longitudinal projections that establish and maintain translamellar inhibition, and to determine whether loss of vulnerable interneurons causes translamellar disinhibition. Other studies will address the role of septal neurons in establishing lamellar hippocampal function. A second hypothesis predicts that synaptic reorganization forms abnormal connections between normally unconnected excitatory hippocampal neurons and that these interconnections give rise to hippocampal seizure discharges. A series of parallel electrophysiological studies in awake, chronically implanted animals will describe for the first time whether spontaneous epileptic seizures arise from the hippocampus, and will utilize a molecular marker of excitation to identify the neurons that are discharging in the most commonly used epilepsy models. Continuous electrophysiological monitoring will also determine the behavior of hippocampal neuron populations before and after injury, before and after injury-induced synaptic reorganization, and before and after the development of spontaneous seizures. New preliminary data indicating that human patients may have a pre-existing region of focal disinhibition will be used to develop several new models of temporal lobe epilepsy. These studies, which utilize a newly developed neurotoxin that selectively removes inhibitory interneurons in a highly focal region, will address the possibility that new animal models that may more closely approximate the human condition may be useful for detecting new pharmacological treatments for what remains a frequently drug-resistant neurological disorder.

Temporal lobe epilepsy is a common neurological disorder characterized by spontaneous neuronal seizure activity that originates within or near the hippocampus. The human epileptic hippocampus exhibits a characteristic pattern of cell loss and a synaptic reorganization of surviving neurons. It is the basic assumption of this application that this pattern of cell loss and the resulting reorganization of neural pathways are in some way causally related to the pathophysiology of this clinical disorder. Electrophysiological and anatomical experiments have been designed to study the possible functional consequences of defects in the structure and function of the hippocampal network. Two animal models that exhibit different . features of the human epileptic state, i.e. cell loss, axon sprouting, and spontaneous seizures, will be carefully characterized and compared. In vivo electrophysiological experiments will utilize hippocampal evoked field potentials to study inhibition and excitability in the whole animal after experimental lesions, both before and after synaptic reorganization occurs. In vitro hippocampal slices from the same animals will be used to study the cellular mechanisms of the pathophysiology identified in the in vivo experiments. The in vivo identification of a pathophysiological defect and its preservation and investigation in vitro is a unique feature of these studies. Intracellular recordings of dentate granule cells pairs and granule cell-basket cell pairs will reveal excitatory-inhibitory interactions in damaged hippocampi, both before and after synaptic reorganization occurs. Light and electron microscopic-immunocytochemical methods will be used to identify synaptically reorganized pathways in terms' of their altered circuitry. Additional studies will attempt to prevent the axon sprouting that follows seizure-induced cell injury in order to elucidate the functional consequences of synaptic reorganization. This will be done by infusion with antibodies to growth factors that are thought to mediate the sprouting response. The long-term goal of the proposed studies is to determine how a disruption in the hippocampal neuronal network leads to the development of hippocampal principal cell hyperexcitability that is likely to be a significant feature of the epileptic state. Identification of the cellular mechanisms that underlie these abnormal network properties will lead to an understanding of the epileptic process and the rational development of new drugs useful in the treatment of this often medically intractable neurological disorder.