Abstracts

RATIONALE: Morphological studies suggest that the primate hippocampus develops extensively before birth. However, as direct recordings from primate neurons have not been performed in utero it is at present not known whether the network is functional at an early developmental stage.
METHODS: We have now performed patch-clamp recordings from hippocampal neurons in slices of monkey fetuses delivered by cesarean section. Neurons were reconstructed and the maturation of axons, dendrites and spines determined quantitatively.
RESULTS: We report that whereas in the beginning of mid gestation many neurons are silent with no functional synapses and little or no dendrites, two months later - a few days before birth- neurons are extensively developed with as many as 7000 spines. This is correlated with a sequential expression of GABAergic and a month later glutamatergic synaptic currents. GABAergic synapses are functional in neurons that have a small apical dendrite in stratum radiatum whereas glutamatergic synapses are only formed in neurons with well- developed apical dendritic arbor displaying spines. Most of the early synaptic activity is provided by internally generated network activity similar to the Giant Depolarizing Potentials (GDPs) observed in neonatal rodents. During the last third of gestation, when all pyramidal neurons have an extensive axonal arbor and a high density of glutamate synapses, the hippocampal network is capable of generating intense epileptiform activity.
CONCLUSIONS: We have shown in earlier studies in rodents that maturation of cortical circuits is associated with three basic rules: i) GABAergic synapses are established first, ii) GABA initially exerts an excitatory action and iii) initial activity is provided by network driven activities. Present results indicate that that these rules have been maintained throughout evolution -and are valid most likely for humans - bu they have been shifted to in utero in primates. The present study demonstrates for the first time that in primate, epileptiform activity can be generated in the hippocampus already in utero. This is important since clinical observations and animal studies have repeatedly demonstrated that epileptiform activities in the neonatal brain - often sub-clinical, i.e. lacking clear clinical manifestations - can result in neurological and behavioral problems in adulthood, including reduction in the seizures threshold and development of temporal lobe epilepsy (Holmes, Ben-Ari, 1998).
References:
Ben-Ari et al, TINS, 1997.
Holmes and Ben-Ari, Neuron, 1998, vol21.
Ben-Ari, TINS, 2001 (june).
Support: INSERM.