engleski

Morpho-functional development of hippocampal glutamatergic and GABAergic neurons

Reorganization, dysfunction and/or cell death of several specific types of neurons including GABAergic interneurons is a hallmark of various psychiatric and neurological diseases such as schizophrenia and epilepsies to which defect in neurogenesis or migration of these neurons can be a predisposing factor. Understanding primate specific developmental mechanisms that regulate the generation, migration, and maturation of cortical neurons is a crucial step to understand such pathologies. Our works have examined, the morpho-functional development of Glutamatergic and GABAergic neurons of the hippocampal formation a structure known to be involved in mesial temporal lobe epilepsy. In the cynomolgus monkey, the first half of prenatal life (term E165) corresponds to the period of massive production of hippocampal neurons including glutamatergic principal cells and GABAergic interneurons, migration of the postmitotic neurons and organization of the main cytoarchitectonic subfields. Neurogenesis of principal cells takes place in the ventricular zone of the dorso-medial telencephalon. Hippocampal GABAergic neurons displayed distinct sites of origin, a primate specific feature. They are generated not only in the proliferative region of the ventral telencephalon, the ganglionic eminence (GE) as in rodents, but also in the proliferative zones of the dorsal-medial telencephalon. Neurogenesis of GABAergic neurons in both ventral and dorsal telencephalon occurs however with different temporal profiles, starting first in the GE and prospective septal region and then in the ventricular zone of the hippocampus and peri-hippocampal region. At midgestation principal neurons as well as many interneurons are very immature with little neuritic extensions except some populations of early-generated interneurons mainly located in the marginal zone. The second half of gestation is characterized by extensive growth and maturation of the cytoarchitectic fields correlated with the morpho-functional development of principal cells and interneurons. The axons and dendrites of pyramidal cells grow intensively by hundreds of micrometers per day. Principal cells acquire dendritic spines. The maturation of the different populations of GABAergic neurons including basket cell, precedes and parallels that of principal cells. Among these populations of interneurons, parvalbumin-containing basket cells are the latest to developed. Synaptic currents on pyramidal neurons appear around midgestation and are correlated with the level of morphological differentiation of these neurons: the first synapses are GABAergic, and their emergence correlates with the growth of apical dendrite into stratum radiatum. A later occurrence of glutamatergic synaptic currents correlates with a further differentiation of the axo-dendritic tree and the appearance of spines. Hundreds of new glutamatergic synapses are established every day on a pyramidal neuron during the last third of gestation. Epileptiform discharges can be evoked by the GABA(A) receptor antagonist bicuculline by the last third of gestation. In conclusion, development of cortical neurons displays unique features in primates such as the dorsal telencephalic origin of cortical GABA neurons. In addition, in contrast to rodents, primate hippocampal formation displays a high level of maturity already at birth.

GABA; glutamate; synapse; circuitry

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