APOPTOSIS AND NECROSIS INDUCED IN DIFFERENT HIPPOCAMPAL NEURON POPULATIONS BY REPETITIVE PERFORANT PATH STIMULATION IN THE RAT

Patients experiencing spontaneous seizures of temporal lobe origin oft en exhibit a shrunken hippocampus, which results from the loss of dent ate granule cells, hilar neurons, and hippocampal pyramidal cells. Alt hough experimental attempts to replicate the human pattern of hippocam pal sclerosis in animals indicate that prolonged seizures cause promin ent injury to dentate hilar neurons and hippocampal pyramidal cells, d entate granule cells of animals are generally regarded as relatively r esistant to seizure-induced injury. By evaluating pathology shortly af ter hippocampal seizure discharges were induced electrically, we disco vered that some granule cells are highly vulnerable to prolonged excit ation and that they exhibit acute degenerative features distinct from those of other vulnerable cell populations. Intermittent perforant pat h stimulation for 24 hours induced acute degeneration of dentate granu le cells, dentate hilar neurons, and hippocampal pyramidal cells. Howe ver, stimulation for 8 hours, which was insufficient to injure hilar n eurons and hippocampal pyramidal cells, was nonetheless sufficient to induce bilateral granule cell degeneration. Degenerating granule cells were consistently more numerous in the infrapyramidal than the suprap yramidal blade, and were consistently more numerous in the rostral tha n caudal dentate gyrus. Depending on the nature of the insult, acutely degenerating neurons exhibit distinct morphological features that are classifiable as either apoptosis or necrosis, although the degree of possible overlap is unknown. Light and electron microscopic analysis o f the acute pathology caused by prolonged afferent stimulation reveale d that degenerating hilar neurons and pyramidal cells exhibited the mo rphological features of necrosis, which is characterized in part by ea rly cytoplasmic vacuolization before nuclear changes occur. However, a cutely degenerating granule cells exhibited the clearly distinct morph ological features of apoptosis, which include an early coalescence of nuclear chromatin into multiple nuclear bodies, compaction of the cyto plasm, cell shrinkage, and budding-off of 'apoptotic bodies' that are engulfed by glia. Whereas pyramidal cell debris persisted for months, granule cell debris disappeared rapidly. This observation may explain why significant granule cell vulnerability has not been described prev iously. These data document for the first time that dentate granule ce lls are among the cell types most vulnerable to seizure-induced injury , and demonstrate that whereas hilar neurons and pyramidal cells under go a typically necrotic degenerative process, granule cells simultaneo usly exhibit morphological features that more closely resemble the deg enerative process of apoptosis. This finding implies that the type of cell death induced by excessive excitation may be determined postsynap tically by the way in which different target cells 'interpret' an exci tatory insult. This experimental model may be useful for identifying t he biochemical mechanisms that initiate and mediate neuronal apoptosis and necrosis, and for developing strategies to prevent or induce thes e presumably distinct forms of neuronal death. (C) 1996 Wiley-Liss, In c.