Infantile hydrocephalus occurs in 3-4% of live births, and although mortality rates are reduced by the placement of ventriculo- peritoneal (VP) shunts, one third of all operated patients continue to suffer from mental retardation, low IQs, spasticity and other motor disorders. Previous studies have demonstrated damage to the periventricular white matter and ependyma, but the neuronal basis for the residual neurologic deficits is currently unknown. Our ULTIMATE OBJECTIVE is to elucidate the effects of infantile hydrocephalus and VP shunts on neuronal development and function. The neurological deficits that can persist in hydrocephalus suggest that neurons may be irreversibly damaged, and in fact, our preliminary results on rats and kittens support the HYPOTHESIS that infantile hydrocephalus does alter the structure of neurons and the levels of neurotransmitters in the cerebral cortex. Most importantly, our initial experiments on hydrocephalic kittens suggest that cytoarchitectural and biochemical deficits are only partially ameliorated by VP shunts. We now propose to extend our preliminary studies on kittens in order to (1) produce an adequate animal model that will permit comprehensive, multidisciplinary analyses, (2) quantitatively evaluate the behavioral and morphological effects of hydrocephalus and (3) determine to what extent reduction of CSF pressure by VP shunts can reduce or alter the effects of hydrocephalus. During the initial phases of the project, hydrocephalus will be induced in 4-10 day old kittens by injection of vaccinia virus or kaolin into the cisterna magna. Both methods will be compared using morphological analyses, and the most appropriate model chosen for future use. Subsequently, experimental, littermate sham-control and intact-control animals will be tested every 5 days for neurologic development and gross motor behavior, and then sacrificed at 5, 10, 25 and 85 days post-operatively (about 10, 15, 30 & 90 days if age). Another group of experimental animals will receive ventricular shunts at 5 and 10 days of age. This shunted group, along with an age-matched control group, will also be tested behaviorally before and after shunt placement, and sacrificed at 15, 30 and 90 days of age. Cerebral cortical tissue from all groups will be processed by Niss1, Haematoxylin and Eosin, Bodian, Golgi and EM methods to provide data on cortical cytoarchitecture, myeloarchitecture, dendritic morphology and ultrastructure. In addition, all animals will be monitored by ultrasonography pre- and post-operatively in order to correlate our results with the severity of hydrocephalus, as well as determine the optimal time for shunting.
