Developmental neurotoxicity of low levels of lead: Cholinergic deficit in the septohippocampal pathway

It has been recently estimated that 9% of preschool children in the United States are at risk for environmental, low level lead exposure. These levels have been associated with lasting learning and memory deficits in children and experimental animals. The integrity of the cholinergic septohippocampal pathway is essential for spatial learning and short-term memory. The pathway is comprised of cholinergic cell bodies in the medial septumivertical diagonal band (MS/vDB) and their axonal projections whose terminals innervate all regions of the hippocampal formation. We investigated the developmental effects of low-level lead exposure on the cholinergic septohippocampal pathway of the rat. Rat pups were exposed to 0.2% lead acetate in the drinking water from embryonic day 16 until postnatal day 31. Exposure to lead caused a 30-35% reduction in activity of cholineacetyltransferase (ChAT), a cholinergic marker enzyme, in the septum and hippocampus. In addition, there was a 34-38% decrease in the density of sodium-dependent high-affinity choline uptake (SDHACU) sites localized exclusively on terminals of cholinergic fibers in the hippocampus. The reduction in the cholinergic markers was observed during early development of the cholinergic septohippocampal pathway and persisted long after termination of lead exposure. The lead-induced deficit in the cholinergic neurochemical markers was associated with a 19-24% reduction of ChAT-immunoreactive cells in the MS/vDB and a long-lasting 14-16% decrease in density of acetylcholinesterase (AChE)-positive fibers in the hippocampus. Lead exposure, however, had no effect on levels of nerve growth factor (NGF), a neurotrophin known to be important for the development, growth and survival of septal cholinergic projection neurons and outgrowth of cholinergic fibers in the hippocampus. These results indicate that perinatal low-level lead exposure interferes with normal development of the cholinergic septohippocampal pathway and induces a long-lasting deficit in cholinergic neurochemical and morphological parameters in the hippocampus. The lead-induced alterations in the cholinergic septohippocampal pathway may contribute to the cognitive deficits associated with early lead exposure.