Compensatory changes in cortical cholinergic innervation in the rat following an immunotoxic lesion

PURPOSE: To investigate the plastic capacity of the cholinergic system in a partial animal model of Alzheimer's disease. METHODS: Rats received unilateral lesions of the horizontal diagonal band of Broca (HDB) using a cholinergic-specific toxin, 192 IgG-saporin. After the appropriate survival time (2, 4, 8, 12 and 24 weeks post-lesion) rats were sacrificed and the brains were prepared for histology. Immunocytochemical and morphometric techniques were employed to quantify the cholinergic neurons surviving the lesion and to measure the density of cortical cholinergic fibers. RESULTS: Cell counts revealed on average a 60% reduction in cholinergic neurons on the lesioned side, compared to the spared side. This cell loss was permanent, that is, there was no significant change in the amount of cell loss over time. In correlation with this cell loss, cholinergic fibers in the target area, the entorhinal cortex (EC), were also reduced such that the density of acetylcholinesterase (AChE)-stained fibers on the lesioned side was 44% of the spared side. The density of cholinergic fibers in the EC increased significantly between 2 and 12 weeks post-lesion (p=0.0216) but remained stable at that level by 24 weeks after the lesion. CONCLUSIONS: Following a cholinergic-specific lesion, a compensatory mechanism is activated in the basal forebrain cholinergic system, such that surviving neurons, projecting to the same target, extend their terminals to occupy the denervated area. It remains to be investigated whether these sprouts are able to establish proper synaptic connections and make a functional recovery in this particular system.