Synapse formation in the human hippocampus

Light microscopic studies of the development of dendrites, and the early appearance of first spines, suggest that synapse formation starts early in the human hippocampal formation. It is extremely difficult to achieve adequate preservation of postmortem fetal or child brains for electron microscopy. Data relating to the synaptic development of the human hippocampal formation are rare. In accord with expectations based on studies of monkey brains (Berger, Alvarez, and Goldman-Rakic, 1993), the first synapses have been observed in the marginal zone and in the cortical subplate of Ammon's horn in a 15-week-old fetus (Kostovic et al., 1989). The axodendritic asymmetric synapses in the marginal zone suggest that entorhinal axons have already reached the hippocampus at that age, since those are the sole excitatory afferents in that zone. Recent findings using anterograde and retrograde tracers indicate that reciprocal entorhinal-hippocampal projections may be among the first corticocortical connections to be established in the human brain (Hev-ner and Kinney, 1996). The perforant pathway projection from the entorhinal cortex to the dentate gyrus develops several weeks later than the connection to Ammon's horn (Hevner and Kinney, 1996). In our electron microscopic preparations of postmortem tissue from neonates (36-40 weeks of gestation), small asymmetric axodendritic and axospinous synapses are frequently found in different layers of the dentate gyrus and Am-

Figure 4.10 Electron micrographs of the hilar region of the newborn infant (A and B) and adult (C). (A) An axon terminal (open star) that forms a symmetric synapse (arrows) with a dendrite in the hilus of the dentate gyrus of a newborn child. (B) A small (star) and a large (mt) terminal in the hilus of the newborn child. Both terminals contain a few vesicles and form asymmetric synapses (arrows and curved arrow) with dendrites. In the mossy terminal (mt) the mitochondria locate away from the synaptic surface and the terminal contains a few dense core vesicles (open arrows). (C) A large mossy fiber terminal (mt) in the hilus of the dentate gyrus of an adult human is fully packed with synaptic vesicles and a few of them contain a dense core (open arrows). Mitochondria locate away from the asymmetric synaptic surface (arrow). Calibration bar = 0.5 |um.

Figure 4.10 Electron micrographs of the hilar region of the newborn infant (A and B) and adult (C). (A) An axon terminal (open star) that forms a symmetric synapse (arrows) with a dendrite in the hilus of the dentate gyrus of a newborn child. (B) A small (star) and a large (mt) terminal in the hilus of the newborn child. Both terminals contain a few vesicles and form asymmetric synapses (arrows and curved arrow) with dendrites. In the mossy terminal (mt) the mitochondria locate away from the synaptic surface and the terminal contains a few dense core vesicles (open arrows). (C) A large mossy fiber terminal (mt) in the hilus of the dentate gyrus of an adult human is fully packed with synaptic vesicles and a few of them contain a dense core (open arrows). Mitochondria locate away from the asymmetric synaptic surface (arrow). Calibration bar = 0.5 |um.

mon's horn (figure 4.10B). However, the large complex mossy fibers terminals seen in the adult dentate gyrus (figure 4.10C) cannot be seen. It is highly probable that those terminals are disrupted and the structure destroyed by the postmortem autolysis, but it is also possible that mature mossy fiber terminals are rare in the newborn infant. There are a few large and pale terminals that display a few vesicles close to the synaptic surface and mitochondria that locate away from the synaptic surface (figure 4.1 OB). These are characteristic of mossy fiber terminals and, as in newborn monkeys, the hilus contains both mature and immature mossy fiber terminals (Seress and Ribak, 1995b). Similarly, as in monkeys (Berger, Alvarez, and Goldman-Rakic, 1995), nonprincipal GABAergic neurons appear to develop very early in the human hippocampal formation. NADPH-d positive neurons appear at the 15th fetal week and become frequent from the 28th to the 32nd weeks (Yan and Ribak, 1997). In accord with light microscopic data, symmetric synapses were frequent in the different layers of the dentate gyrus (figure 4.10A) and Ammon's horn in newborn children.

In summary, the first afferent fibers to the hippocampus proper arise from the entorhinal cortex and establish synapses with neurons of Ammon's horn early in fetal development (Kostovic et al., 1989). This corresponds to the suggestion of Berger, Alvarez, and Goldman-Rakic (1993) that the remarkably early maturation of the entorhinal cortex during the first half of gestation, together with the early neurochemical development of the hippocampal formation, indicates that functional circuits in primates form during the first half of gestation. Tracing studies also suggest that entor-hinal-hippocampal connections are established by mid-gestation (Hevner and Kinney, 1996). In addition, the presence of the following indirect features suggests that neuronal connections of the inner trisynaptic circuit of the hippocampus, which connect the dentate gyrus with the entorhinal cortex, are also established prenatally: ( 1 ) mature-looking granule cells present in the dentate gyrus at birth give rise to richly arborizing axons; (2) small thorny excrescences on dendrites of mossy and CA3 pyramidal cells in newborn children; (3) asymmetric synapses in the dentate gyrus and in the stratum lucidum of Ammon's horn of newborn children; (4) a large number of asymmetric synapses in the strata ra-diatum and oriens of the CA1 area of Ammon's horn. Therefore, it is reasonable to assume that children born at term have the synaptic connections necessary to establish memory traces (for discussion, see Nelson, 1995). However, the functional capability of those circuits has not been fully examined. One must be extremely cautious when correlating morphology with function, either at the electrophysiological or behavioral level. For instance, Purpura (1975) demonstrated that immature photic-evoked potentials can be recorded in 33-week-old premature infants whose pyramidal cells in the visual cortex have poorly developed basal dendrites and almost no spines. Despite the fact that the adult-like neuronal circuitry needed for information processing was absent, some synaptic connections were nevertheless capable of transmitting visual impulses. It is plausible that similar events occur in the hippocampal formation, and thus the earliest forms of memory formation may not necessarily be related to the adult-like function of the hippocampal formation.

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