Neurotransmitters and neuromodulators during early human development.
BACKGROUND
Neurotransmitters such as monoamines appear in the embryo before the neurones are differentiated. They may have other functions than neurotransmission during embryogenesis such as differentiation and neuronal growth. For example, serotonin may act as a morphogen. A number of neuropeptides are expressed during ontogenesis, but their function has been difficult to establish. Maybe some of them remain as evolutionary residues. Fast-switching neurotransmitters like the excitatory amino acids and the more ionotropic receptors dominate in the human brain, but appear probably later during evolution as well as during ontogeny.


METHODS
The distribution of catecholamines during development has been analysed with a fluorescence method, while most of the other neurotransmitters have been mapped with immunohistochemical methods. The classical method to determine the physiological role of a neurotransmitter or modulator is to study the physiological effect of its antagonist, blocking the endogenous activity. By transgenic technique, the genes encoding for enzymes involved in the synthesis of neurotransmitters can be knocked-out.


RESULTS
Pharmacological blocking of endogenous activity has, for example, demonstrated that adenosine suppresses fetal respiration. Knocking out the dopamine beta-hydroxylase gene results in fetal death, suggesting that noradrenaline is essential for survival. Some neurotransmitters change their effect during embryogenesis, e.g. GABA which is excitatory in the embryo, but inhibitory after birth due to a switch from a high to low chloride content in the nerve cells. It is possible that this is of importance for the wiring of neuronal network in early life. NMDA receptors dominate in the foetus, while kainate and AMPA receptors appear later. At birth, there is a surge of neurotransmitters such as catecholamines, which may be of importance for the neonatal adaptation.


CONCLUSIONS
Neurotransmitters and modulators are not only important for the neural trafficking in the embryo, but also for the development of the neuronal circuits. Prenatal or neonatal stress (hypoxia), as well as various drugs, may disturb the wiring and cause long-term behavioural effects (fetal and neonatal programming).
Herlenius
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E
Neonatal Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska Institutet, S-171 76 Stockholm, Sweden.
Lagercrantz
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H
D000328:Adult; D000818:Animals; D001921:Brain / Q000196:embryology; D002648:Child; D002675:Child, Preschool; D004622:Embryo, Mammalian / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000502:physiology*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018377:Neurotransmitter Agents / Q000502:physiology*; D011247:Pregnancy; D051381:Rats
D018377:Neurotransmitter Agents