Acetylcholinesterase (AChE)-containing axons are the only extrinsic fibers projecting to the adult cortex that readily innervate embryonic cortical grafts up to normal densities without prior manipulation of the host brain. In the present paper we compare the time course of AChE-positive fiber innervation in the normal mouse cortex with that seen in neocortical grafts by using AChE histochemistry as a marker for presumed cholinergic fibers. Donor tissue was taken at two different stages of gestation; before (embryonic days 12-14, or E12-14) and after (E17-19) the cortical plate is formed. Three features are analyzed: 1) the distribution and density of AChE-containing fibers, 2) the presence of AChE-positive cells, and 3) the distribution of butyrylcholinesterase (BuChE)-positive elements. The modification of Koelle's method used for AChE localization showed AChE-positive fibers in developing parietal neocortex as early as E18-19. The distribution of AChE-labeled fibers in the normal cortex achieves the mature pattern by the end of the third postnatal week. The rate of innervation of transplants takes longer and depends on the age of the donor tissue. Tissue from both donor ages first showed AChE-positive fibers crossing the host-transplant interface by 7 days postsurgery. E17-19 tissue approaches the density of AChE-positive fibers in the normal adult cortex by 15 weeks after grafting, whereas the E12-14 donor tissue does not approach normal innervation densities until after 20 weeks. While the degree of innervation in the E12-14 donor tissue never equalled the surrounding adult cortex within our range of survival times, a few of the E17-19 transplants did develop densities equal to that of the host cortex. AChE-positive cells are first detectable in the normal parietal cortex on the day of birth, peak by the end of the first postnatal week, and then decline in number to the low levels of the mature cortex after the second postnatal week. Grafted cells in E12-14 tissue stain lightly for AChE by 7 days postsurgery, achieve maximal densities by 3 weeks, and become markedly reduced in number and density by 10 weeks. Cells in E17-19 tissue are lightly reactive by 7 days postsurgery, reach maximal numbers by 2 weeks postsurgery, and become similar in number and density to those seen in the mature cortex after 4 weeks. The appearance of BuChE-reactive blood vessels, neurons, and glia in both normal development and in the transplants is described and discussed.(ABSTRACT TRUNCATED AT 400 WORDS)