Prenatal development of nicotinamide adenine dinucleotide phosphate-diaphorase activity in the human hippocampal formation.

Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry was used to study the development of the neurons metabolizing nitric oxide in the prenatal human hippocampal formation. Strongly reactive non-pyramidal neurons appeared in small numbers in the subplate at 15 weeks, and rapidly increased in this layer, as well as the cortical plate-derived layers between 17 and 24 weeks. The marginal zone also had a few NADPH-d cells at 15 weeks. The pattern of these darkly reactive cells stabilized by 28 weeks, with the somata distributed mostly at the border of the cortex and white matter in the entorhinal cortex and subiculum, or the alveus in Ammon's horn. Moderately stained non-pyramidal neurons appeared in the dentate gyrus by 17 weeks, and increased in this region and Ammon's horn up to 28 weeks. Small, lightly reactive non-pyramidal neurons were first seen by 32 weeks and increased in number by term. They were mainly distributed in layers II/III of the entorhinal cortex and stratum pyramidale of the subiculum and Ammon's horn. NADPH-d positive fibers in the marginal zone were mostly thin and developed between 20 and 28 weeks. In other cortical layers, thick processes from the darkly stained NADPH-d neurons appeared first, then fine fibers appeared more numerous, especially after 28 weeks. NADPH-d processes that arose from non-pyramidal cells were frequently apposed to blood vessels, including those in the hippocampal fissure. In addition, NADPH-d reactivity was also present in pyramidal and granule cells, but this staining was most pronounced between 15 and 24 weeks. The results show three types of distinctly stained NADPH-d interneurons in the fetal human hippocampal formation with different developmental courses and morphology. Also, hippocampal principal neurons transiently express NADPH-d at early fetal ages. Our data correlated with other findings suggest that nitric oxide may play a role in neuronal development in the hippocampal formation by modulating neuronal differentiation and maturation, and regulating blood supply.