RECIPROCAL ENTORHINAL-HIPPOCAMPAL CONNECTIONS ESTABLISHED BY HUMAN FETAL MIDGESTATION

Little is known about the timing or sequence of genesis of connections between different areas of the developing human cerebral cortex. It h as been shown that connections between areas V1 and V2 of the visual i socortex are established at about 37 weeks of gestation (Burkhalter [1 993] Cerebr. Cortex 3:476-487), suggesting that cortico-cortical conne ctions appear late in the 40-week human gestational period. However, t here are indications from other studies that connections between subdi visions of the hippocampal formation may be established much earlier, by about 20 weeks of human gestation. To Investigate this possibility, the lipophilic bidirectional tracer 1,1' dioctadecyl-3,3,3',3-tetrame thylindocarbocyanine perchlorate (DiI) was used to study connections b etween the entorhinal cortex, hippocampus, and temporal lobe neocortex in paraformaldehyde-fixed postmortem fetal tissue. The DiI transport revealed robust reciprocal connections between the entorhinal cortex, hippocampus, and subiculum, which were consistently present at 19 week s of gestation (the earliest age studied), and which were anatomically similar to those in adult primates. Specifically, projections to the hippocampus and subiculum originated from neurons in the entorhinal co rtex (EC) layers 2 and 3, whereas reciprocal projections to the EC ori ginated from pyramidal neurons in the cornu ammonis region CA1 and the subiculum. In contrast, the perforant pathway projection from EC to t he dentate gyrus, and all connections with the neocortex, reached only rudimentary stages of development by 22 weeks of gestation (the lates t age studied). These findings suggest that hippocampal pathways devel op prior to isocortical pathways, and that reciprocal entorhinal-hippo campal projections may be among the first cortico-cortical connections to be established in the human brain. (C) 1996 Wiley-Liss, Inc.