Fate of the hippocampal mossy fiber projection after destruction of its postsynaptic targets with intraventricular kainic acid.

Intraventricular injections of kainic acid were used to create a model of selective cell death in order to study the fate of afferent projections that are deprived of their postsynaptic targets. This treatment rapidly destroyed hippocampal CA3 pyramidal cells, but not those neurons that give rise to their mossy fiber and entorhinal afferents. Light microscopic studies with the Timm's sulfide silver stain indicated that half or more of the mossy fiber boutons in area CA3b were lost within the first 1-3 days after kainic acid administration. This finding was confirmed by electron microscopy. Electron-dense, usually vacuolated mossy fiber boutons accounted for about 10-20% of the total population present at a 4-hour survival time, but were not encountered in control rats nor at survival times longer than 1 day. Other mossy fiber boutons remained electron lucent, but enlarged, became more rounded in shape, and suffered an apparent loss of synaptic vesicles. It is suggested that degeneration of some mossy fiber boutons and resorption of others into the axon may have accounted for the precipitous decline in their number. The dendritic excrescences contacted by these boutons were nearly all undergoing electron-dense degeneration 4 hours after kainic acid administration. In rats that survived 6-8 weeks mossy fiber boutons remained somewhat scarce, individual boutons appeared relatively small, and only one-third the normal percentage were observed to be engaged in more than one synaptic contact within a single cross section. A qualitative electron microscopic study of the entorhinal projection to area CA3 suggested a response to kainic acid treatment similar to that of the mossy fiber projection, except that no entorhinal boutons were seen to become electron dense. These findings suggest that presynaptic fibers in the mature hippocampus adjust the size of their terminal arborizations and number of synaptic contacts to accommodate a reduction in the target cell population. The rapid loss of mossy fiber boutons may be attributable to an unusual fragility of these structures when they are deprived of the mechanical support normally provided by the pyramidal cell. Finally, the ability of kainic acid administration to alter the number and distribution of presynaptic elements must be taken into account whenever this toxin is used to make selective lesions of postsynaptic cells.

Duke Scholars

Author J. Victor Nadler Pharmacology & Cancer Biology