Age-related effects of triphenyl phosphite-induced delayed neuropathy on central visual pathways in the European ferret (Mustela putorius furo)

The objective of this study was to investigate the relationship between the maturation of visual system neurons and the onset of their susceptibility to triphenyl phosphite (TPP)-induced delayed neurotoxicity in the European ferret. We administered single subcutaneous doses of TPP (1184 mg/kg body wt) to 1- to 10-week-old ferret kits to assess the effects on connections and neurons of the developing lateral geniculate thalamic nucleus (LGN) and primary visual cortex. Brains were processed with a modified Fink-Heimer silver-impregnation method. Axonal and terminal degeneration were first noted in the LGN of kits injected at 5 weeks of age. The severity of the degeneration increased in kits injected at later ages and reached adult densities and configurations in ferrets injected at 10 weeks of age. Degenerating neuronal cell bodies were also present in the LGN of kits injected at 7 weeks of age and older. In the visual cortex, axonal and terminal degeneration were consistently present in kits injected at 8 weeks of age and attained adult-like densities in kits injected at 10 weeks of age. Previous studies have reported that the ferret visual system appears to reach anatomical maturity (as defined by mature LGN lamination patterns, the location and density of axon terminals originating from neurons in the retina and LGN, and the migration and synaptic connections of cortical neurons) by 4-5 weeks of age. A temporal comparison of these normal developmental data with the degeneration data obtained in the present study suggests that immature neurons in the visual system of the ferret are not susceptible to TPP-induced delayed neurotoxicity but only become so after they have achieved some degree of maturity. Whether the LGN neurons undergoing degeneration are directly affected by TPP or are showing a transneuronal response to loss of afferent input remains unresolved.