Human fetal hippocampal development: I. Cytoarchitecture, myeloarchitecture, and neuronal morphologic features

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Abstract
To characterize better the process of anatomic development of the human hippocampus, we studied the cytoarchitecture, myeloarchitecture, and neuronal morphology in human fetal and postnatal hippocampi. Twenty cases were studied in which the ages ranged from 9 weeks gestation through 62 years. Fixed, paraffin-embedded, hippocampal sections were stained with cresyl violet for Nissl substance and immunolabeled for myelin basic protein. The hippocampal region at 9 weeks contains 4 layers: a ventricular zone, an intermediate zone, a homogeneous-appearing hippocampal plate comprised of bipolar-shaped neurons, and a wide marginal zone. At 15–19 weeks, individual subfields can be distinguished. A distal-to-proximal gradient of cytoarchitectural and neuronal morphologic maturity is seen, with the subiculum appearing more developed than the ammonic subfields and the dentate gyrus appearing least mature. Within each subfield, an “inside-out” gradient of maturity is also evident. By 32–34 weeks gestational age, neurons in CA2 and CA3 have undergone rapid enlargement and morphologic maturation, surpassing CA1, which still contains some immature neurons. The dentate gyrus is the latest area to develop, only assuming a mature cytoarchitecture after 34 weeks. The essential cytoarchitectural appearance of the hippocampal subfields is stable after birth, although there is progressive neuronal enlargement and a decrease in neuronal density throughout childhood into adulthood. Myelination is first evident near term, with strong myelin basic protein immunoreactivity present in the angular bundle, alveus, and fimbria and relatively scant immunoreactivity in the nascent perforant pathway. Myelination in the hippocampus increases in childhood until adolescence, after which the pattern remains unchanged. These studies delineate normal neuroanatomic development and can be used to understand better the mechanisms underlying human neurodevelopmental and neurodegenerative disorders of the hippocampal formation.