Neurobiology of Soman

This report documents progress in an ongoing study of the central effects of organophosphate 0P poisoning. In previous work, we have described the anatomy and physiology of a model central cholinergic system, the projection from the horizontal limb of the diagonal band HDB to the main olfactory bulb. These basic studies have led to experiments described in the present Report, which focus more directly on the mechanisms of 0P-induced seizures. We have used the proto-oncogene c-fos, a marker for neural hyperactivity or cellular stress, to determine the location of early signs of seizure damage after a single sublethal dose of the 0P, soman. In rats exhibiting behavioral convulsions, but not in non-convulsive rats, c-fos was present in specific layers of the piriform cortex 30 min after injection with soman. At later times, c-fos could be found in other cortical structures. Since piriform cortex is the structure suffering the most obvious damage after soman intoxication, this finding suggests that c- fos expression is a reliable marker for the early stages of neural damage and that seizures begin in piriform cortex and spread to other brain structures. Astrocytes have long been known to be involved in the response to injury of the CNS. The importance of these cells in the response to injury has been recently emphasized by the discovery of a marker specific to astrocytes, glial fibrillary acidic protein GFAP. We have used this marker to demonstrate that astrocytes are activated soon after the onset of seizures. We also demonstrated significant large decreases in levels of norepinephrine NE. Thus, we examined the brainstem source neurons of these transmitters for c-fos expression following soman intoxication.