Cholinergic fiber perturbations and neuritic outgrowth produced by intrafimbrial infusion of the neurofilament-disrupting agent 2,5-hexanedione

The compound 2,5-hexanedione (HD) produces axonopathies in peripheral nerves characterized by selective accumulation of neurofilaments. Its direct actions on neurotransmitter-specific neurons in the brain are unknown. In an attempt to address this latter issue, we infused HD into the fimbria and evaluated histochemically and immunohistochemically possible structural alterations in cholinergic neurons projecting from the basal nuclear complex to the hippocampus. Putative cholinergic fibers expressing nerve growth factor receptor and acetylcholinesterase showed increases in caliber and perturbations in trajectories 2–4 days following HD treatment. Similar morphologic changes were observed in neuronal elements processed for the 68 kDa neurofilament protein. At 7 days, short collateral ramifications appeared in many cholinergic axons that were suggestibe of neurite outgrowth. Correlated with these fiber alterations was a transient reduction in the number of medial septal and diagonal band somata expressing choline acetyltransferase, which returned to control levels within 6 weeks following HD treatment. These data support the view that neurofilaments play an important, perhaps cytoarchitecturally stabilizing, role in regulating axonal morphology in certain populations of cholinergic neurons.