TRANSNEURONAL DEGENERATION IN THE CENTRAL NERVOUS SYSTEM

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The longterm goal of this research is to determine the mechanisms which underlie the vulnerability of developing neurons to degeneration. Damage to the central nervous system results in primary retrograde degeneration of axotomized neurons. Subs equent transneuronal degeneration can occur to involve neurons across one or two synapses. Both primary and transneuronal degeneration are more likely to follow injury to the developing nervous system than when comparable injury occurs in the adult. In the neonatal cat, ablation of visual cortex results in primary degeneration of cells in the dorsal lateral geniculate nucleus (dLGN) and transneuronal degeneration of beta retinal ganglion cells. When visual cortex is ablated in the adult cat, cells in the dLGN degenerate whereas all cells in the retina survive. These results would seem to show that cells are vulnerable to transneuronal degeneratation only during the period before they and their synaptic connections have reached maturity. However, although primary degeneration occurs following visual cortex ablation at any age, the speed and severity of this degeneration varies between young and adult animals. Therefore, it is unclear at present whether neurons are susceptible to transneuronal degeneration because of their immaturity or whether transneuronal degeneration is dependent on the characteristics of the primary degeneration. The experiments in this proposal are designed to test the hypothesis that transneuronal degeneration is a process to which only developing neurons are vulnerable. First, a model for rapid primary degeneration in the adult dLGN will be developed using the neurotoxin kainic acid. This model will thus deprive mature retinal ganglion cells of their normal target cells in a similar way to visual cortex ablation in the neonate. This will be used to investigate the consequences of rapid degeneration in the adult dLGN by studying retinal projections and connectivity in the dLGN, as well as the survival of different ganglion cell populations. The results from these experiments will provide information essential to the interpretation of previous work and to the direction of future research into the mechanisms of neuronal degeneration. The experiments will use standards light and electron microscopy techniques to label neuronal pathways and quantify aspects of synaptic connectivity.