Neuronal Distribution of Phosphate Activated Glutaminase in the Human Epileptogenic Hippocampus.
Abstract number :
2.024
Submission category :
Year :
2001
Submission ID :
1707
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
T. Eid, M.D., Ph.D., Neurosurgery, Yale University School of Medicine, New Haven, CT; O.P. Ottersen, M.D., Ph.D., Anatomy, University of Oslo, Oslo, Norway; D.D. Spencer, M.D., Neurosurgery, Yale University School of Medicine, New Haven, CT; I.A. Torgner,
RATIONALE: An overabundance of transmitter glutamate has been implicated in the pathogenesis of temporal lobe epilepsy (TLE). Increased extracellular levels of glutamate have indeed been demonstrated in sclerotic hippocampi of TLE patients, while those patients without sclerosis had relatively lower levels of hippocampal glutamate (During MJ and Spencer DD, Lancet 1993; 341:1607-10). In the latter group, the hippocampus is not believed to be the focus of the seizures. We propose that the elevated levels of glutamate in the sclerotic hippocampus is due to an increased expression and/or an ultrastructural redistribution of the glutamate synthesizing enzyme, phosphate activated glutaminase (PAG).
METHODS: Hippocampal specimens were obtained from patients that underwent surgical intervention for medically intractable TLE. Based on the histological appearance and the immunohistochemical distribution of somatostatin, neuropeptide Y and dynorphin, the resected hippocampi were classified into two experimental groups: (1) sclerotic and (2) non-sclerotic. Sections from each group were immunostained with a highly specific antibody against PAG and examined in the light microscope. Small blocks of tissue were also freeze-substituted, embedded in Lowicryl, and processed for high-resolution immunogold electron microscopy.
RESULTS: In both patient categories, PAG-immunoreactivity (ir) was preferentially localized to neurons in all hippocampal subfields. Fewer PAG-immunoreactive neurons were present in the sclerotic hippocampi, particularly in the hilus, CA3, and CA1, as compared to the non-sclerotic hippocampi. On the ultrastructural level, PAG-ir was enriched to the mitochondrial compartment of neurons.
CONCLUSIONS: This first high-resolution immunocytochemical study of PAG in the human hippocampus confirms previous biochemical data that PAG is localized to neuronal mitochondria. The data suggest that mechanism(s) other than an increased expression of PAG-containing cells are responsible for the elevated levels of glutamate in the sclerotic hippocampus. Such mechanisms could involve a redistribution of PAG from the mitochondria to the cytosol.
Support: NIH 5P01NS39092-02. Research Council of Norway (NFR).