Developmental cholinotoxicity of lead: loss of septal cholinergic neurons and long-term changes in cholinergic innervation of the hippocampus in perinatally lead-exposed rats.

The effects of perinatal lead exposure on choline acetyltransferase-immunoreactive (ChAT-IR) cell counts in the medial septum and AChE-positive fiber counts in the hippocampus were examined in relation to changes in cholinergic markers in the septohippocampal pathway of the rat. Maternal exposure to 0.2% lead acetate in drinking water from gestational day 16 through weaning at post-natal day 21 (P21) induced in the offspring a 30% reduction in septal ChAT activity and a 20% reduction in ChAT-IR cell profile counts in the medial septum/vertical diagonal band (MS/vDB). These changes were seen as early as P7, persisted through 2 months post-exposure (P81), and were followed by recovery of ChAT activity but not the ChAT-IR cell numbers, at 3 months post-exposure (P112). The loss of ChAT activity and ChAT-IR neurons in the septum was temporally associated with a reduction of ChAT activity (30%), hemicholinium-3 (HC-3) binding (40%), and AChE-positive fiber counts (13-15%) in the hippocampus. The hippocampal ChAT activity and AChE-positive fiber counts returned to control levels by P112 whereas HC-3 binding was restored to normal levels by P200. These results indicate that perinatal, low-level lead exposure induces loss of septohippocampal cholinergic projection neurons in neonate animals, resulting in a deficit in hippocampal cholinergic innervation that persists into young adulthood. The disruption of cholinergic septohippocampal system may be an important factor in lasting cognitive impairments associated with early Pb exposure.